\r\n\tb) how a concentrated attention focus on screens (i.e., tablets and smartphones) could result in a total activity absorption and a flow experience; \r\n\tc) teens' preference for media social interaction appears to be closely associated with impaired modes of mood regulation; \r\n\td) the web activities as factors of externalized and/or internalized risks; \r\n\te) the implementation of health promotion interventions by Internet Apps; finally, \r\n\tf) the cross-cultural differences and similarities about teen approaches to the web around the world.
\r\n
\r\n\tThis book intends to provide the reader with an overview of studies with a research topic that is crucial today: the need to integrate teens' use of the web into the processes contributing to determine adolescents' developmental trajectories and Quality of Life.
",isbn:"978-1-83969-594-0",printIsbn:"978-1-83969-593-3",pdfIsbn:"978-1-83969-595-7",doi:null,price:0,priceEur:0,priceUsd:0,slug:null,numberOfPages:0,isOpenForSubmission:!0,hash:"f005179bb7f6cd7c531a00cd8da18eaa",bookSignature:"Prof. Massimo Ingrassia and Prof. Loredana Benedetto",publishedDate:null,coverURL:"https://cdn.intechopen.com/books/images_new/10671.jpg",keywords:"Media Multitasking, Brain Development, Optimal-Experience Conditions, Digital Media Use, Mood Self-Regulation, Social Networking, Health Risk Behaviors, Internalizing/Externalizing Risk, Health Behaviors, Prevention, Cross-Cultural Research, Teen",numberOfDownloads:null,numberOfWosCitations:0,numberOfCrossrefCitations:null,numberOfDimensionsCitations:null,numberOfTotalCitations:null,isAvailableForWebshopOrdering:!0,dateEndFirstStepPublish:"February 25th 2021",dateEndSecondStepPublish:"March 24th 2021",dateEndThirdStepPublish:"May 23rd 2021",dateEndFourthStepPublish:"August 11th 2021",dateEndFifthStepPublish:"October 10th 2021",remainingDaysToSecondStep:"21 days",secondStepPassed:!1,currentStepOfPublishingProcess:2,editedByType:null,kuFlag:!1,biosketch:"Massimo Ingrassia is Director of the Post-graduate Advanced Studies in Palliative care and pain management for psychologists and a scientific advisor in research projects assessing psychological adjustment and therapeutic adherence in chronic illness. He was the author or co-author of several articles, and editor of the books on Parenting.",coeditorOneBiosketch:"Loredana Benedetto, Ph.D., is a psychologist and professor of Developmental and Educational Psychology at the Department of Clinical and Experimental Medicine, University of Messina. She was a scientific consultant for projects supporting families of the disabled and interventions in pediatric palliative care.",coeditorTwoBiosketch:null,coeditorThreeBiosketch:null,coeditorFourBiosketch:null,coeditorFiveBiosketch:null,editors:[{id:"193901",title:"Prof.",name:"Massimo",middleName:null,surname:"Ingrassia",slug:"massimo-ingrassia",fullName:"Massimo Ingrassia",profilePictureURL:"https://mts.intechopen.com/storage/users/193901/images/system/193901.png",biography:"Massimo Ingrassia, PsyD, is an Associate Professor of Developmental and Educational Psychology at Messina University, Italy, where he teaches graduate and postgraduate courses in Health Psychology. He is the Director of the postgraduate advanced studies in Palliative Care and Pain Management for Psychologists. His research interests include risk behaviors in adolescence and emerging adulthood, childhood development and digital technologies, pediatric palliative care and family resilience, and quality of life and chronic diseases. Dr. Ingrassia is also a scientific advisor for research projects assessing psychological adjustment and therapeutic adherence in chronic illness. He is the author or coauthor of several articles and books, including Growing Connected: Web’s Resources and Pitfalls",institutionString:"University of Messina",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"2",totalChapterViews:"0",totalEditedBooks:"0",institution:{name:"University of Messina",institutionURL:null,country:{name:"Italy"}}}],coeditorOne:{id:"193200",title:"Prof.",name:"Loredana",middleName:null,surname:"Benedetto",slug:"loredana-benedetto",fullName:"Loredana Benedetto",profilePictureURL:"https://mts.intechopen.com/storage/users/193200/images/system/193200.png",biography:"Loredana Benedetto, Ph.D., is a psychologist and Professor of Developmental and Educational Psychology at the Department of Clinical and Experimental Medicine, University of Messina, Italy. She teaches undergraduate and graduate courses in the areas of typical and atypical development, parent-child relationships, educational psychology, and family-based interventions. She has been a scientific consultant for projects supporting families of disabled children and interventions in pediatric palliative care. Her research interests focus on parenting assessment, self-efficacy and parental cognition, digital parenting and problematic use of the Internet in children, metacognition and childhood disorders, early intervention in autism and developmental disabilities, and behavioral parent training. She is the author or editor of several books, including Parenting: Empirical Advances and Intervention Resources (coedited with Massimo Ingrassia).",institutionString:"University of Messina",position:null,outsideEditionCount:0,totalCites:0,totalAuthoredChapters:"3",totalChapterViews:"0",totalEditedBooks:"2",institution:{name:"University of Messina",institutionURL:null,country:{name:"Italy"}}},coeditorTwo:null,coeditorThree:null,coeditorFour:null,coeditorFive:null,topics:[{id:"21",title:"Psychology",slug:"psychology"}],chapters:null,productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"},personalPublishingAssistant:{id:"205697",firstName:"Kristina",lastName:"Kardum Cvitan",middleName:null,title:"Ms.",imageUrl:"https://mts.intechopen.com/storage/users/205697/images/5186_n.jpg",email:"kristina.k@intechopen.com",biography:"As an Author Service Manager my responsibilities include monitoring and facilitating all publishing activities for authors and editors. From chapter submission and review, to approval and revision, copyediting and design, until final publication, I work closely with authors and editors to ensure a simple and easy publishing process. I maintain constant and effective communication with authors, editors and reviewers, which allows for a level of personal support that enables contributors to fully commit and concentrate on the chapters they are writing, editing, or reviewing. I assist authors in the preparation of their full chapter submissions and track important deadlines and ensure they are met. I help to coordinate internal processes such as linguistic review, and monitor the technical aspects of the process. As an ASM I am also involved in the acquisition of editors. 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\n
1. Introduction
\n
Thiamine or vitamin B1 consists of a thiazole/thiazolium ring [5-(2-hydroxyethyl)-4-methylthiazole, THZ] linked by a methylene bridge to an aminopyrimidine ring (2-methyl-4-amino-5-hydroxymethylpyrimidine, HMP) (Figure 1A). Thiamine diphosphate (ThDP) is the best-known form of thiamine, as it is a cofactor. Other natural thiamine phosphate derivatives include: thiamine monophosphate (ThMP), thiamine triphosphate (ThTP), adenosine thiamine triphosphate (AThTP) and adenosine thiamine diphosphate (AThDP) (Figure 1A) [1, 2]. These latter forms have yet to be analyzed in archaea and, thus, will not be a focus of this review.
\n
Figure 1.
Thiamin (vitamin B1) and its natural forms. A) Thiamin and its natural derivatives thiamin monophosphate (ThMP), thiamin diphosphate (ThDP), thiamin triphosphate (ThTP), and adenosine thiamin triphosphate (AdThTP). The aminopyrimidine ring (blue), thiazolium ring (red) and methylene bridge (green) are highlighted with carbon indicated by C or blue balls. B) Thiamin diphosphate and its C2 anion/ylid form (ThDP-). Enzyme bound ThDP is in a V-conformation, which positions the 4′-amino group of the pyrimidine to abstract the C2-H proton of the thiazolium ring when activated by a conserved glutamate residue of the enzyme (in red). The two resonance structures of the anion/ylid are presented.
\n
\n
\n
2. Thiamine diphosphate
\n
ThDP is an enzyme cofactor found in all domains of life. In archaea and bacteria, ThDP is considered one of the eight universal cofactors along with NAD, NADP, FAD, FMN, S-adenosyl-methionine (SAM), pyridoxal-5-phosphate (PLP, vitamin B6), CoA and the C1 carrier tetrahydrofolate or tetrahydromethanopterin [3]. The rare exceptions are the bacteria Borrelia and Rickettsia, which do not use ThDP as a coenzyme for metabolism [4].
\n
ThDP-dependent enzymes catalyze the cleavage and formation of C-C, C-N, C-S and C-O bonds in a wide range of catabolic and anabolic reactions [5]. As a coenzyme, ThDP serves as an electrophilic covalent catalyst in the decarboxylation of 2-oxo acids (e.g., pyruvate and 2-oxoglutarate) and in carboligation and lyase-type reactions [6, 7, 8]. The active species of ThDP is typically the C2 anion/ylid (ThDP−) form, generated by dissociation of the C2-H proton from the thiazole ring (Figure 1B). ThDP− is the source of the catalytic power of ThDP-dependent enzymes, as it can add to unsaturated systems and serve as a sink for mobile electrons [9, 10]. ThDP typically requires Mg2+ or Ca2+ ions to bind the enzyme in a V conformation in which the 4′-amino group of the pyrimidine ring is positioned to abstract the C2-H proton from the thiazole ring (Figure 1B) [11, 12, 13, 14, 15]. This proton abstraction is often assisted by a conserved glutamate residue (Glu) of the enzyme that provides a carboxylate side chain for hydrogen bonding to the N1’ of the pyrimidine ring and for proton relay to form the ThDP− catalytic intermediate (Figure 1B). Thus, ThDP is fundamentally distinct among coenzymes in that both rings contribute to catalysis.
\n
ThDP-dependent enzymes are used in pyruvate metabolism, the TCA cycle, the pentose phosphate pathway and branched chain amino acid biosynthesis (Table 1). Archaea commonly use ThDP-dependent 2-oxoacid: ferredoxin oxidoreductases (OFORs) to catalyze the oxidative decarboxylation of 2-oxoacids (e.g., pyruvate, 2-oxoglutarate and 2-oxoisovalerate) into an energy rich CoA thioester [16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32] or the reverse reaction to fix CO2 into cell carbon [33]. ThDP, Mg2+ and Fe-S cluster(s) are the intrinsic cofactors of OFORs with ferredoxin as the electron acceptor. OFORs (typically 270 kDa) are less complex than the 5-6 MDa 2-oxoacid dehydrogenases (ODHs) of mitochondria and aerobic bacteria; ODHs rely upon NAD+ as the electron acceptor and are composed of E1p (ThDP-dependent 2-oxoacid decarboxylase), E2p (lipoate acetyltransferase) and E3p (dihydrolipoamide dehydrogenase) components [16]. While some archaea express mRNAs specific for all three ODH (E1p, E2p and E3p) homologs, ODH activity has yet to be detected in archaea [30]. Other ThDP-dependent enzymes of archaea include the non-oxidative 3-sulfopyruvate decarboxylase of coenzyme M biosynthesis [34, 35] and the acetohydroxyacid synthase of branch-chain amino acid (isoleucine, leucine and valine) biosynthesis [36, 37]. The transketolase activities of archaea [38] are presumed to be catalyzed by ThDP-dependent enzymes based on comparative genomics [39].
Thiamin diphosphate (ThDP)-dependent enzymes and their distribution among the three domains of life. Enzyme homolog detected (+), not detected (n.d.), or low homology (?) as indicated.
\n
\n
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3. Thiamine biosynthesis de novo
\n
Thiamine is synthesized de novo by generating thiazole and aminopyrimidine rings separately and then joining the rings to form ThMP, the precursor of ThDP. The de novo pathways rely upon energy input (ATP), carbon- and nitrogen-based intermediates and a source of sulfur (the latter incorporated into the thiazole ring).
\n
\n
3.1. Synthesis and phosphorylation of the aminopyrimidine ring of thiamine
\n
ThiC (HMP-P synthase; EC 4.1.99.17) is the major enzyme used by bacteria [40, 41], plant chloroplasts [42] and archaea [43] to synthesize the aminopyrimidine ring of thiamine (Figures 2-4). ThiC converts 5′-phosphoribosyl-5-aminoimidazole (AIR) to 4-amino-5-hydroxymethyl-2-methylpyrimidine phosphate (HMP-P), thus, diverting carbon/nitrogen skeletons of purine metabolism to thiamine biosynthesis. ThiC is a radical SAM enzyme, that initiates this catalytic reaction by use of a [4Fe-4S]+ cluster that reductively cleaves SAM to methionine and an 5′-deoxyadenosyl radical [40], a presumed oxidizing cosubstrate of the reaction [44].
\n
Figure 2.
Thiamin (vitamin B1) biosynthesis in bacteria. Enzymes are discussed in text and colored by phylogenetic distribution (red, restricted to one domain of life; blue, found in all domains of life; green, apparent homologs in all domains of life but no direct evidence). Abbreviations: AIR, 5-aminoimidazole ribotide; SAM, S-adenosyl-methionine; GAP3P, D-glyceraldehyde 3-phosphate; HMP-P, 4-aminohydroxymethyl-2-methylpyrimidine phosphate; HMP-PP, 4aminohydroxymethyl-2-methylpyrimidine diphosphate; ThMP, thiamin monophosphate; ThDP, thiamin diphosphate; DXP, 1-deoxy-D-xylulose 5-phosphate; cTHZ-P, 2-[(2R,5Z)-2-carboxy-4-methylthiazol-5(2H)-ylidene]ethyl phosphate; THZ-P, 4-methyl-5-(β-hydroxyethyl)thiazolium phosphate; X, electron carrier.
\n
Figure 3.
Thiamin (vitamin B1) biosynthesis in eukaryotes. Blue shading indicates restricted to yeast. Abbreviations: ADP-thiazole, ADP-5-ethyl-4methylthiazole-2-carboxylate; PLP, pyridoxal phosphate; R5P, D-ribose 5-phosphate.?, not determined to date. For additional abbreviations and coloring scheme see Figure 2.
\n
Figure 4.
Thiamin (vitamin B1) biosynthesis in archaea. For abbreviations and coloring scheme see Figures 2, 3.
\n
THI5 forms the aminopyrimidine ring of thiamine from the substrates PLP and histidine in yeast [45, 46] (Figure 3). Only a subset of THI5 family (IPR027939) proteins have the conserved histidine residue needed for HMP-P synthesis [45] and appear restricted to yeast, fungi, plants (non-chloroplast) and select γ-proteobacteria. Bacterial ABC-type solute binding proteins for HMP precursor (ThiY) [47] and riboflavin (RibY) [48] transport are structurally related to THI5. Thus, the archaeal THI5 family proteins, which are devoid of the conserved histidine residue, are suggested to serve a similar role in transport.
\n
ThiD domain proteins are used as bifunctional HMP kinase (EC 2.7.1.49)/HMP-P kinase (EC 2.7.4.7) enzymes in thiamine biosynthesis and salvage (Figures 2-4). Bacterial ThiD [49, 50] and yeast THI20 and THI21 (N-terminal ThiD domain proteins) [51] phosphorylate HMP-P to HMP-PP in the de novo pathway and successively phosphorylate HMP to HMP-PP in the salvage pathway. Proteins with an unusual ThiD2 domain (standalone or fused to ThiE) are identified in bacteria to catalyze only HMP-P kinase activity, potentially to avoid misincorporation of damaged and/or toxic analogs of HMP into ThDP-dependent enzymes [52]. ThiD homologs (IPR004399) are widespread in all domains of life, including organisms that only salvage HMP and do not synthesize thiamine de novo. Archaeal ThiD proteins are standalone or fused to a ThiN-type ThMP synthase domain (see later discussion) [43, 53, 54].
\n
\n
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3.2. Synthesis of the thiazole ring of thiamine
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De novo biosynthesis of the thiazole ring can be classified into two fundamentally distinct pathways based on the type of thiazole synthase (ThiG vs. Thi4) used. While similar in nomenclature, the ThiG- and Thi4-type thiazole synthases differ in terms of structure and function. The ThiG-dependent pathway relies upon at least six steps to form THZ-P and appears limited to bacteria based on the phylogenetic distribution of ThiG (EC 2.8.1.10) (Figure 2). By contrast, the Thi4-type branch for thiazole biosynthesis is simpler in having only two steps (Figures 3-4) and appears more widespread, as Thi4-homologs (KEGG K03146) are represented in all domains of life and are demonstrated to function in thiazole ring biosynthesis in yeast [55] and archaea [56, 57].
\n
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3.2.1. Synthesis of the thiazole ring of thiamine by the ThiG-pathway
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To form the thiazole ring, ThiG uses three substrates: () dehydroglycine, (ii) 1-deoxy-D-xylulose-5-phosphate (DXP) and (iii) thiocarboxylated ThiS [58, 59, 60, 61] (Figure 2).
\n
(i) Dehydroglycine is synthesized by either oxygen-dependent (ThiO; EC 1.4.3.19) or SAM radical enzymes (ThiH; EC 4.1.99.19), both of which are broadly distributed in bacteria but generally absent in archaea and eukaryotes. The ThiO glycine oxidase catalyzes the oxidative deamination of glycine to form the dehydroglycine required for thiazole ring synthesis [62, 63, 64, 65]. By contrast, the ThiH tyrosine lyase forms a 5′-deoxyadenosyl radical that initiates cleavage of the C alpha-C beta bond of tyrosine to generate the dehydroglycine (needed for thiamine biosynthesis) and p-cresol (the byproduct) [66, 67, 68].
\n
(ii) The 1-deoxy-D-xylulose-5-phosphate synthase (Dxs; EC 2.2.1.7) is a ThDP-dependent enzyme that condenses the (hydroxyethyl)-group derived from pyruvate with the C1 aldehyde group of D-glyceraldehyde 3-phosphate (GAP3P) to generate DXP and CO2 [69, 70]. Dxs homologs (IPR005477) are widespread in bacteria, green algae, higher plants and protists but rare in archaea. Dxs generates the DXP precursor of thiamine, pyridoxol and non-mevalonate isoprenoid biosynthesis pathways [69, 70]. DXP is used for thiamine biosynthesis in bacteria but not in eukaryotes or archaea (Figure 2).
\n
(iii) The ThiG-dependent pathway uses a protein-based relay system to mobilize sulfur to the thiazole ring. Sulfur is transferred from L-cysteine to an active site cysteine residue of a sulfurtransferase (e.g., IscS-SH) [71] to form an enzyme persulfide intermediate (e.g., IscS-S-SH) [72]. In a separate reaction, the E1-like ThiF adenylates the C-terminus of the ubiquitin-fold protein, ThiS, in a mechanism resembling the activation step of ubiquitination [73]. This modification step readies the C-terminus of ThiS for thiocarboxylation. The sulfur is relayed from IcsS-S-SH to ThiS through the ThiI rhodanese (RHD) domain [71, 74, 75, 76]. The resulting thiocarboxylated ThiS serves as the sulfur donor for the ThiG mediated synthesis of the thiazole ring [58, 59, 60, 61].
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3.2.2. Synthesis of the thiazole ring of thiamine by the Thi4-pathway
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The Thi4-pathway used to form the thiazole ring (Figures 3, 4) is distinct from that of ThiG (Figure 2). Key to the pathway is Thi4-mediated formation of ADP-thiazole, which is then hydrolyzed to THZ-P by a presumed NUDIX hydrolase [55]. Thi4 family (IPR002922) proteins are distributed in all domains of life and generally absent from ThiG-containing bacteria. Although initially annotated as ribose-1,5-bisphosphate isomerases (R15Pi) based on indirect assay [77], archaeal Thi4 homologs are found to be distinct from archaeal R15Pi of the e2b2 family [78, 79] and demonstrated to catalyze thiazole synthase activity [56] that is transcriptionally repressed when thiamine and THZ levels are sufficient [43] and is required for thiazole ring formation [57]. In vitro, yeast Thi4 operates by a suicide mechanism by mobilizing the sulfur of its active site cysteine (C205) to form ADP-thiazole from NAD and glycine [55]. By contrast, the methanogen Thi4, uses an active site histidine residue and iron to catalyze the synthesis of ADP-thiazole from NAD, glycine and sulfide [56]. Thi4 enzymes of archaea, yeast [80] and plant [81] are related based on X-ray crystal structure; in addition, yeast Thi4 modified to use an active site histidine residue can operate by a catalytic mechanism with iron similarly to the methanogen Thi4 [56, 80].
\n
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3.2.3. Condensation of the aminopyrimidine and thiazole rings to form ThMP
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Once formed, the thiamine ring precursors (i.e., THZ-P and HMP-PP) are condensed to ThMP by a ThMP synthase of the ThiE- or ThiN-type (EC 2.5.1.3).
\n
ThiE-type ThMP synthases are widespread in all domains of life (IPR036206) and are found to catalyze the substitution of the diphosphate of HMP-PP with THZ-P to yield ThMP, CO2 and diphosphate (PPi) in bacteria [82, 83], plants [84] and yeast [85]. ThiE homologs are often bifunctional, fused to an additional catalytic domain such as HMP-P kinase (EC 2.7.4.7) [52, 84, 85]. ThiE serves as a ThMP synthase in certain archaea based on its requirement for growth of haloarchaea in the absence of thiamine, HMP and/or THZ [43].
\n
ThMP synthases of the ThiN-type are also identified in archaea and bacteria, but absent in eukaryotes. ThiN domain (IPR019293) proteins are of three major types: I) fused to an N-terminal DNA binding domain (ThiR type), II) fused to an N- or C-terminal catalytic domain (e.g., ThiD) and III) standalone ThiN domains. The ThiDN proteins are ThMP synthases based on in vitro assay and complementation of ΔthiE mutants for growth in the absence of thiamine [43, 53, 54]. Fusion of the ThiN domain to the HMP/HMP-P kinase domain (ThiD) is suggested to minimize the release of HMP-PP prior to its condensation with THZ-P and, thus, channel substrate to the ThMP product [43]. ThiN domains that lack a conserved α-helix near the active site histidine are not ThMP synthases and instead can serve as apparent ligand binding sites for transcriptional regulation as in ThiR (see later discussion) [43].
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3.2.4. Formation of ThDP from ThMP or thiamine
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Thiamine diphosphate (ThDP), the biologically active form of thiamine, is produced from ThMP by two routes. ThMP is commonly phosphorylated to ThDP by the ATP-dependent ThiL ThMP kinase (EC 2.7.4.16 of IPR006283) in bacteria [86] and archaea [87]. Alternatively, ThMP is hydrolyzed to thiamine, and thiamine, is converted to ThDP by a Mg2+-dependent thiamine pyrophosphokinase TPK (THI80) that catalyzes thiamine + ATP ⇆ ThDP + AMP (EC 2.7.6.2) in eukaryotes [88, 89, 90, 91]. Consistent with this latter route, TPK is required for the de novo biosynthesis of thiamine in yeast [89, 90] and the ThMP phosphatase TH2 can hydrolyze ThMP to thiamine in plants [92]. TPK is also used to salvage thiamine to ThDP in eukaryotes [91, 93] and certain bacteria (TPK homolog YloS) [93]; by contrast, γ-proteobacteria use a thiamine kinase (ThiK, EC 2.7.1.89) to phosphorylate thiamine to ThMP [93] prior to ThiL-mediated phosphorylation of ThMP to ThDP. While TPK (IPR036759) homologs are conserved in some archaea, ThiK is not. Puzzling then is that certain archaea (e.g., haloarchaea and Pyrobaculum) have ThiBQP thiamine transport and ThiL ThMP kinase homologs but do not have ThiK or TPK homologs or activities (e.g., Pyrobaculum californica) [87]. Furthermore, archaea lacking TPK and ThiK homologs can transport thiamine and generate ThDP as demonstrated by growth of a ThMP synthase mutant, Haloferax volcanii ΔthiE, when supplemented with thiamine but not THZ or HMP [43, 57]. These findings suggest that certain archaea use an alternative pathway to salvage thiamine to ThDP.
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4. Thiamine transport
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Thiamine is a micronutrient that is actively transported into cells against a concentration gradient. Transport of thiamine and its precursors alleviates the need for de novo biosynthesis of thiamine. Thiamine transporters are predicted in archaea based on homology to bacterial transport systems or identification of putative transporter genes that are either in genomic synteny with thiamine biosynthesis genes or downstream of ThDP-binding riboswitch (THI- box) motifs [57, 94, 95, 96].
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Bacterial transporters of thiamine and thiamine precursors, conserved in archaea, can be classified into: (i) ABC-type transporters (e.g., ThiBPQ and ThiYXZ) [47, 97, 98], (ii) a new ABC-type class termed energy coupling factor (ECF) importers [95, 99], (iii) NiaP transporters [100] of the major facilitator superfamily (MSF, IPR036259) that use an ion gradient [101] and (iv) PnuT transporters that mediate the facilitated diffusion of thiamine [102, 103]. ABC and ECF are primary active transporters that hydrolyze ATP in thiamine uptake by use of conserved ATPases (Figure 5). ECF and ABC transporters are distinguished by the type of protein used to bind solute: ECF uses a transmembrane substrate-capture protein (S component, ThiT) while ABC uses an extracytoplasmic solute binding protein (e.g., ThiB or ThiY) [95, 99]. ECF systems are typically modular in that ThiT and other S-components (e.g., the biotin specific BioY) interchangeably bind to the transmembrane (T) component of the system [95, 99, 104]. By comparison, ABC systems are not modular and have solute binding proteins (ThiB/Y) that bind to the extracytoplasmic domain of the transporter [47, 48, 105, 106].
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Figure 5.
Comparison of thiamin transport by ABC and ECF importers. The nucleotide-binding domains that hydrolyze ATP and drive transporter are shown in blue. The ABC-type transmembrane domain protein (ThiP) and ECF-type Tcomponent (EcfT) are in shades of green. The soluble binding protein (ThiB, ThiY) of the ABC importer is in dark orange. The ECF importer S-components of thiamin (ThiT) and biotin (BioY), which can be swapped, are in shades of orange.
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5. Thiamine salvage
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Thiamine and its derivatives are salvaged from the outside and inside of a cell to replenish and repair the ThDP cofactor for metabolism. Thiamine salvage pathways are widespread in all domains of life and overcome the need for de novo biosynthesis of thiamine, minimize energy cost, and reduce the misincorporation of thiamine breakdown products into ThDP-dependent enzyme active sites [107].
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Archaea are found to salvage thiamine and its derivatives (HMP and THZ) from the environment [43, 57] and repress the de novo biosynthesis of thiamine when thiamine levels are sufficient [43, 108]. Archaeal salvage pathways are predicted to include enzymes of de novo biosynthesis (i.e., ThiD, ThiE or ThiDN, and ThiL) with enzymes specific for salvage such as ThiM (THZ kinase, EC 2.7.1.50), TenA (aminopyrimidine aminohydrolase, EC 3.5.99.2) and/or YlmB (formylaminopyrimidine deformylase, EC 3.5.1.-) the latter speculative as it clusters to a family of proteins (IPR010182) that includes succinyl-diaminopimelate desuccinylase and YodQ of N-acetyl-beta-lysine synthesis [57] (Figure 6). ThiM is a THZ kinase in bacteria [49, 109, 110, 111], protists [112], and plants [113] and is predicted in archaea (e.g., UniProtKB D4GV40) based on conserved active site residues [114]. TenA homologs are subclassified into TenA_C and TenA_E [115], based on conserved active site cysteine and glutamate residues, respectively. Both types of TenA proteins are conserved in archaea. TenA_C is demonstrated to be an aminohydrolase that works in concert with the YlmB deformylase to regenerate HMP from thiamine degradation products and to function as a thiaminase II that hydrolyzes thiamine to THZ and HMP in bacteria [94, 116]. Note that thiaminase I (EC 2.5.1.2) which is secreted by certain bacteria to degrade thiamine [117, 118] is distinct from TenA. In plants, TenA_E is bifunctional in catalyzing deformylase and aminohydrolase activities to regenerate HMP from thiamine breakdown products, thus, overcoming the need for YlmB [115]. TenA_C and TenA_E are conserved in archaea and likely to function in thiamine salvage.
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Figure 6.
Thiamin (vitamin B1) salvage in archaea. Abbreviations: Formylaminio-HMP, N-formyl-4-amino5-aminomethyl-2-methylpyrimidine; amino-HMP, 4amino-5-aminomethyl-2-methylpyrimidine; HMP, 4amino-5-hydroxymethyl-2-methylpyrimidine; THZ, 4methyl-5-(2-hydroxyethyl)thiazole. For additional abbreviations and coloring scheme see Figures 2-4.
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6. Thiamine regulation
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Thiamine biosynthesis, salvage and/or transport pathways are regulated by THI-box riboswitches in bacteria [119, 120, 121], eukaryotes [122, 123, 124, 125], and a few archaea (based on Rfam RF00059) [43, 96]. The THI-box riboswitch is a regulatory element of an mRNA/pre-mRNA aptamer that binds a thiamine metabolite and an expression platform that transduces the ligand binding to control gene expression [126]. In bacteria, when ThDP levels are sufficient, ThDP binds the 5′ untranslated region (UTR) of the THI-box and triggers the formation of a stem-loop structure that masks the Shine-Dalgarno (SD) sequence of the mRNA and inhibits translation initiation [119, 120, 121]. The major targets of this regulation are the mRNAs of the thiamine metabolic operons (e.g., thiCEFSGH and thiMD in E. coli) [119, 120, 121] and the ABC-type thiamine transporter (thiBPQ), with the latter based on motif analysis (Rfam RF00059). Eukaryotes (plants, fungi, and algae) also use a THI-box riboswitch to regulate expression of thiamine metabolism but do so by modulating the alternative splicing of pre-mRNAs [42, 122, 123, 124, 125, 127, 128, 129, 130]. In these eukaryotic systems, ThDP or HMP-PP binds the THI-box riboswitch of an intron located in the 5′- or 3’-UTR and causes mispairing of the splice donor (GU) and acceptor (AG) of the pre-mRNA (e.g., THIC and THI4). This incorrect pairing promotes alternative mRNA slicing and, thus, reduces thiamine biosynthesis.
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Thiamine metabolism is also regulated by transcription factors, as exemplified by organisms that synthesize thiamine de novo but do not have a THI-box riboswitch motif including yeast and many archaea. In yeast, three proteins (Thi2p, Thi3p, and Pdc2p) coordinate the induction of thiamine biosynthetic (THI) gene expression in response to thiamine starvation [131, 132, 133, 134, 135, 136]. Thi3p serves as the thiamine sensor for the two transcription factors (Thi2p and Pdc2p) that bind specific DNA sequences upstream of the THI genes. When thiamine is low, Thi3p forms a ternary complex with Thi2p and Pdc2p that activates transcription of the THI genes. Once the levels of thiamine are sufficient, Thi3p binds ThDP, triggering dissociation of Thi3p from the ternary complex and reduced expression of the THI genes. In archaea from the phyla Euryarchaeota [43] and Crenarchaeota [108], a novel transcription factor, ThiR, is found to repress thiamine metabolic gene (thi4 and thiC) expression when the levels of thiamine are sufficient. ThiR is composed of an N-terminal DNA binding domain and C-terminal ThiN domain. The ThiN domain of ThiR is not catalytic, as it is missing an α-helix extension and conserved Met near the active-site His that are needed for the thiazole synthase activity of ThiDN proteins [43]. Instead the ThiN domain of ThiR serves as an apparent sensor of thiamine metabolites that triggers ThiR-mediated repression of thi4 and thiC transcription during thiamine sufficient conditions. This type of transcriptional regulation appears common in archaea based on the widespread phylogenetic distribution of ThiR homologs vs. THI-box motifs.
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7. Future perspectives and conclusions
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Thiamine is an important vitamin for improving human health [137], is a strategic nutritional supplement [138, 139], is targeted for production in probiotics [140], is useful in drug discovery including developing antimetabolites to treat cancer or fungal infections [141, 142, 143, 144], has potential for use as antitoxic agent in the food industry [145], may improve crop resistance [146], is a starting point for design of novel riboswitches [147], functions in central metabolism and unusual biocatalytic reactions [6, 7, 8, 148, 149, 150, 151], may modulate global nutrient cycles [152], and holds promise for other applications.
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Discovery of the metabolic route for the de novo biosynthesis of thiamine in archaea opens a new window for the use of extremophiles in thiamine-related biotechnology applications. Archaea are designated as GRAS (generally recognized as safe) by the FDA, are amenable to genetic manipulation [153], and can readily express ThDP-dependent enzymes from foreign systems (e.g., bacterial pyruvate decarboxylase) [154]. Thus, archaea provide a useful resource to discover and optimize ThDP-dependent biocatalysts for the generation of renewable fuels and chemicals.
\n
Archaea also provide an evolutionary perspective on the origins of thiamine biosynthesis pathways. The aminopyrimidine biosynthesis branch, composed of the radical SAM enzyme ThiC and the HMP/HMP-P kinase ThiD, appears ancient based on its functional conservation in all three domains of life. By contrast, thiazole biosynthesis can be divided into two major pathways: ThiG- and Thi4-dependent. Of these two divisions, the Thi4-type is suggested to be fairly ancient as Thi4 depends on Fe for catalytic activity, can use sulfide as a source of sulfur for thiazole ring formation, is functionally conserved in archaea and eukaryotes, and is predicted to function in certain bacteria (including anaerobes) based on genome sequencing.
\n
Identification of genes needed to transport, synthesize, and salvage thiamine (from the three domains of life) improves understanding of how vitamin B1 may be trafficked in the environment. Finding that Thi4 is important for thiazole ring formation in eukaryotes and archaea provides new perspective on defining the organisms that synthesize thiamine de novo. Microbes that produce thiamine and thiamine precursors are suggested to be of benefit to other microbial taxa that cannot produce thiamine yet require this vitamin as a cofactor for their metabolic activity [152]. Thus, interspecies vitamin transfer may influence the metabolism of microbial consortia and global/carbon energy cycles.
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Finally, thiamine is damaged by extreme conditions such as oxidation. Plant and yeast have a hydrolase (Tnr3, YJR142W) that converts the oxy- and oxo-damaged forms of ThDP into monophosphates to avoid misincorporation of the damaged thiamine molecules into the ThDP-dependent enzymes [155]. Many archaea thrive in conditions of extreme thermal and oxidative stress suggesting these microbes use unique mechanisms to avoid and/or repair damaged ThDP for use as a cofactor.
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Acknowledgments
\n
Funds for this project were awarded to JM-F through the Bilateral NSF/BIO-BBSRC program (NSF 1642283), the U.S. Department of Energy, Office of Basic Energy Sciences, Division of Chemical Sciences, Geosciences and Biosciences, Physical Biosciences Program (DOE DE-FG02-05ER15650) and the National Institutes of Health (NIH R01 GM57498).
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Conflict of interest
The author has no conflict of interest to declare.
\n',keywords:"thiamine, vitamin B1, archaea, thiazole, thiazolium, pyrimidine, sulfur mobilization, riboswitch",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/61444.pdf",chapterXML:"https://mts.intechopen.com/source/xml/61444.xml",downloadPdfUrl:"/chapter/pdf-download/61444",previewPdfUrl:"/chapter/pdf-preview/61444",totalDownloads:798,totalViews:457,totalCrossrefCites:2,totalDimensionsCites:3,hasAltmetrics:0,dateSubmitted:"February 12th 2018",dateReviewed:"April 11th 2018",datePrePublished:"November 5th 2018",datePublished:"September 26th 2018",dateFinished:null,readingETA:"0",abstract:"Thiamine is the water-soluble sulfur containing vitamin B1 that is used to form thiamine diphosphate (ThDP), an enzyme cofactor important in the metabolism of carbohydrates, amino acids and other organic molecules. ThDP is synthesized de novo by certain bacteria, archaea, yeast, fungi, plants, and protozoans. Other organisms, such as humans, rely upon thiamine transport and salvage for metabolism; thus, thiamine is considered an essential vitamin. The focus of this chapter is on the regulation and metabolism of thiamine in archaea. The review will discuss the role ThDP has as an enzyme cofactor and the catalytic and regulatory mechanisms that archaea use to synthesize, salvage and transport thiamine. Future perspectives will be articulated in terms of how archaea have advanced our understanding of thiamine metabolism, regulation and biotechnology applications.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/61444",risUrl:"/chapter/ris/61444",book:{slug:"b-group-vitamins-current-uses-and-perspectives"},signatures:"Julie A. Maupin-Furlow",authors:[{id:"245529",title:"Prof.",name:"Julie",middleName:null,surname:"Maupin-Furlow",fullName:"Julie Maupin-Furlow",slug:"julie-maupin-furlow",email:"jmaupin@ufl.edu",position:null,institution:{name:"University of Florida",institutionURL:null,country:{name:"United States of America"}}}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Thiamine diphosphate",level:"1"},{id:"sec_3",title:"3. Thiamine biosynthesis de novo",level:"1"},{id:"sec_3_2",title:"3.1. Synthesis and phosphorylation of the aminopyrimidine ring of thiamine",level:"2"},{id:"sec_4_2",title:"3.2. Synthesis of the thiazole ring of thiamine",level:"2"},{id:"sec_4_3",title:"3.2.1. Synthesis of the thiazole ring of thiamine by the ThiG-pathway",level:"3"},{id:"sec_5_3",title:"3.2.2. Synthesis of the thiazole ring of thiamine by the Thi4-pathway",level:"3"},{id:"sec_6_3",title:"3.2.3. Condensation of the aminopyrimidine and thiazole rings to form ThMP",level:"3"},{id:"sec_7_3",title:"3.2.4. Formation of ThDP from ThMP or thiamine",level:"3"},{id:"sec_10",title:"4. Thiamine transport",level:"1"},{id:"sec_11",title:"5. Thiamine salvage",level:"1"},{id:"sec_12",title:"6. Thiamine regulation",level:"1"},{id:"sec_13",title:"7. Future perspectives and conclusions",level:"1"},{id:"sec_14",title:"Acknowledgments",level:"1"},{id:"sec_17",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'Bettendorff L, Wins P. Thiamine diphosphate in biological chemistry: New aspects of thiamine metabolism, especially triphosphate derivatives acting other than as cofactors. The FEBS Journal. 2009;276(11):2917-2925\n'},{id:"B2",body:'Frederich M, Delvaux D, Gigliobianco T, Gangolf M, Dive G, Mazzucchelli G, et al. Thiaminylated adenine nucleotides. Chemical synthesis, structural characterization and natural occurrence. 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FEMS Microbiology Reviews. 2011;35(4):577-608\n'},{id:"B154",body:'Kaczowka SJ, Reuter CJ, Talarico LA, Maupin-Furlow JA. Recombinant production of Zymomonas mobilis pyruvate decarboxylase in the haloarchaeon Haloferax volcanii. Archaea. 2005;1(5):327-334\n'},{id:"B155",body:'Goyer A, Hasnain G, Frelin O, Ralat MA, Gregory JF 3rd, Hanson AD. A cross-kingdom Nudix enzyme that pre-empts damage in thiamine metabolism. The Biochemical Journal. 2013;454(3):533-542\n'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Julie A. Maupin-Furlow",address:"jmaupin@ufl.edu",affiliation:'
Department of Microbiology and Cell Science, Institute of Food and Agricultural Sciences, University of Florida, Gainesville, Florida, USA
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1. Introduction
Mycobacterium leprae (M. leprae) is an acid fast bacilli that is the causative agent of leprosy disease which mainly effects the skin and peripheral nerves. In olden times leprosy was common in temperate climates (e.g. Europe), today it is mainly confined to tropical and subtropical regions. Mode of transmission in leprosy is mainly through inhalation of droplets containing the bacteria. But skin contact is also claimed by many leprologists. The disabilities and deformities associated with leprosy due to neuropathy leads to long-term consequences, including. This in turn is associated with stigma.
The immunity of the host plays an important role in disease progress and control. Thus, fortunately 95% of patients exposed to M. leprae will not develop this disease. The variation in incubation period ranges from 2 to 20 years, or even longer.
Leprosy has been successfully eliminated as a public health problem in 2000 globally and at the national level in 113 countries out of 122 by 2005 [1]. Elimination of leprosy is defined by World Health Organization as a point prevalence below 1 per 10,000 population [2]. However, the number of new patients diagnosed with leprosy is still significant, at more than 200,000 in 2016 globally. The new case detection rate of the disease (NCDR) is only slowly declining (Figure 1) [3].
Figure 1.
Trend in case detection and case detection rate, by WHO region, 2006–2016 [3].
The long incubation period, silent symptoms, long duration MDT and unavailability of effective vaccine makes this disease difficult to identify, treat and eradicate. To add to the misery the stigma associated with the disease is another challenge. In such circumstances, prevention and control of disease gains utmost importance.
2. Burden of disease
In 2017, 192,713 patients were on treatment globally which makes the prevalence rate of 0.25 per 10,000 population [4]. Total of 210,671 new cases were reported in same year from 150 countries making NCDR of 2.77 per 100,000 population. Figure 2 below shows the trends over the past decade (2008–2017) in new case detection of leprosy cases globally in the reporting countries of World Health Organization (WHO) [4].
Figure 2.
Country-wise trends of detection of new leprosy cases from 2008 to 2017 [4].
3. Control of leprosy
The three main goals of control of leprosy are
To detect the pathology early and treat the patient completely.
To prevent the transmission to the others.
To prevent the disabilities and other complications.
Thus the following modalities are adopted to control leprosy:
Medical measures
Social support
Program management
Evaluation
4. Medical measures
4.1 Estimation of the burden of leprosy
The control of leprosy starts with the estimation of size and magnitude of the problem. Most common epidemiological survey method of collection of data is “Quick random sample survey.” Information about the prevalence of leprosy, age and sex-wise distribution, various forms of leprosy and the health facilities available should be gathered. Roughly the total prevalence of leprosy in an area would be about 4 times that of the cases found among school children [5, 6]. These estimates are essential to plan, implement and to evaluate the results of the control program.
4.2 Early Case Detection
The objective is to detect all the cases as early as possible and to register them. Active case finding is important as the disease is symptomless in the early stages. Cases can be detected by the Contact surveys, Group surveys and Mass surveys. Contact surveys consists of examination of all household contacts with a lepromatous case, particularly children, in areas with prevalence less than 1 per 1000. Contact surveillance of households is recommended for a minimum period of 10 years after case is declared bacteriologically negative, and for 5 years in households with a non-lepromatous case from the time of diagnosis of the index case. Group surveys are done in areas where prevalence of leprosy is more than 1 in 1000 population. This consists of screening certain groups such as school children, slum dwellers, military recruits, industrial workers, etc. through “Skin camps.” Lastly, mass surveys consists of examination of each and every individual by house-to-house visits in hyperendemic areas (prevalence – 10 or more per 1000 population). These are generally carried out by repeated annual examinations of school children which yield better results at relatively low cost [5, 6]. The data of each case is entered in the standardized proforma developed by WHO.
4.3 Chemotherapy
Since an effective vaccine is unavailable for leprosy the secondary prevention (early treatment) becomes more important. Until 1981, Dapsone (Diamino Diphenyl Sulphone—DDS) was used to treat leprosy which resulted in the development of resistance and relapse, making leprosy control difficult.
Multidrug Therapy: In 1982, WHO recommended Multidrug Therapy (MDT) for all leprosy patients. Introduction of MDT has opened a new avenue in the control of leprosy in the world. Aim of MDT is to convert the infectious case into noninfectious as soon as possible, so as to reduce the reservoir of infection in the community.
The main objectives of MDT are:
To ensure early detection of the cases.
To interrupt the transmission of infection.
To prevent drug resistance, relapse and reaction.
The advantages of MDT over dapsone monotherapy are:
Shorter duration of treatment,
Better patient compliance,
High cure rate,
Cost-effectiveness and
Ease in health delivery system.
There are two types of MDT regimens used depending on the symptoms and signs shown by the patients - Paucibacillary (PB) and Multibacillary (MB). Recommended Regimens are discussed below [3, 5, 6, 7]:
i. Multibacillary leprosy:
MDT is recommended for following groups of patients:
All smear positive cases.
Skin lesions more than five in number.
More than one nerve trunk thickening.
All cases of relapse/reactivation and all cases who have been treated with Dapsone monotherapy earlier.
The drugs used in Multibacillary MDT and dosages are:
Rifampicin: 600 mg once monthly, supervised.
Dapsone: 100 mg daily, self administered.
Clofazimine: 300 mg once monthly, supervised and 50 mg daily, self administered.
Duration of treatment for Multibacillary leprosy is 12 months, can be extended to 18 months and continued where possible up to smear negativity. Sometimes LL/BL patients with high bacilli may need 2–3 years or more of MDT for achieving bacteriological negativity.
ii. Paucibacillary leprosy:
The drugs and dose schedule is:
Rifampicin 600 mg once a month for 6 months supervised.
Dapsone 100 mg daily for 6 months self administered.
Paucibacillary leprosy is treated for 6 months.
MDT is not contraindicated in patients with HIV infection.
Each MDT blister pack contains tablets for 4 weeks treatment. For easy identification color coding of the blister pack is done, that is, with different colors for multibacillary and paucibacillary cases both in adults and children.
The treatment in both PB and MB cases varies depending on the age of the patient. The patients between 10 to 14 years are treated as paediatric cases, while >14 years are considered adult. The standard treatment regimen for MB leprosy in adults is given for 12 months. The drugs in each blister pack are (Figure 3):
Two capsules of Rifampicin of 300 mg (600 mg once a month) to be taken as single dose under supervision.
Clofazimine 3 capsules of 100 mg each to be consumed once a month as single dose under supervision and 50 mg daily for next 28 days.
Dapsone 100 mg as single dose and then daily once for 1 month.
Figure 3.
MDT for adult MB type of leprosy [2, 7].
The standard adult treatment regimen for PB leprosy is (Figure 4):
Rifampicin: 600 mg once a month.
Dapsone: 100 mg daily.
Duration: 6 months (6 blister packs of 28 days each).
Figure 4.
MDT for adult PB type of leprosy [2, 7].
Treatment regimen for MB leprosy in children (ages 10–14 years) is (Figure 5):
Rifampicin: 450 mg once a month.
Clofazimine: 150 mg once a month, and 50 mg every other day.
Dapsone: 50 mg daily.
Duration: 12 months (12 blister packs of 28 days each).
Figure 5.
MDT for pediatric MB type of leprosy [2, 7].
Treatment regimen for PB leprosy in children (ages 10–14 years) is (Figure 6):
Rifampicin: 450 mg once a month.
Dapsone: 50 mg daily.
Duration: 6 months (6 blister packs of 28 days each).
Figure 6.
MDT for pediatric PB type of leprosy [2, 7].
MDT is provided free-of-charge globally through an agreement between a pharmaceutical company and WHO. WHO manages distribution of MDT to countries in coordination with national leprosy programs.
5. Surveillance
Clinical surveillance of the patients after completion of treatment is an important part of MDT to ensure complete cure. For paucibacillary cases follow up for at least once a year for 2 years after completion of treatment and for multibacillary cases at least once a year for 5 years [3, 4, 5].
6. Immunoprophylaxis
Early diagnosis of cases, aggressive treatment and proactive measures to avoid complications and disabilities is the backbone for the success of any comprehensive program. In addition to accurate reporting and control measures, effective preventions will be needed to achieve elimination. Search for an effective vaccine either to be used alone or in combination with a drug has been going for a long time.
Presently BCG (Bacillus Calmette-Guerin) is the only vaccine that has shown some protection against M. leprae bacillus. A single dose of BCG gives 50 percent or higher protection against the disease. It is the most widely used vaccine in the world, yet the degree of protection it confers is not yet confirmed. The meta-analysis of many experimental studies concludes that the vaccine gives approximately 26% protection against leprosy. But the protection level decreases with time. To overcome this problem more than one dose of vaccine is advised.
Other variants of vaccination are also suggested.
Adding killed M. leprae to BCG: Various modifications have been suggested, such as the addition of killed M. leprae to BCG. This method almost doubles the vaccine efficacy in some populations as concluded by few studies. But the same cannot be said for patients below 15 years.
Vaccination with M. indicus pranii (Mycobacterium W): This strain discovered in India. Testing of the MIP vaccine took place in 2005 and showed that it was effective for seven to 8 years, after which a booster dose would be needed to maintain the immunity. Recently the vaccine was approved by the Drug Controller General of India to be rolled out in a project involving five districts in the states of Bihar and Gujarat, where there are high rates of leprosy. Leprosy patients and their close contacts will benefit from this project, making India the first country in the world to have a large-scale leprosy vaccination initiative [8].
Another milestone in prevention of leprosy is the discovery of the vaccine candidate, called LepVax. Scientists at Infectious Disease Research Institute (IDRI), along with national and international collaborators including the National Hansen’s Disease Program and the National Institute of Allergy and Infectious Diseases (NIAID), part of the National Institutes of Health, with financial support from American Leprosy Missions, have developed this leprosy vaccine. Based on the preclinical studies, the LepVax, has progressed to Phase I clinical testing in the United States, the first stage of safety testing in human volunteers. The clinical trial is focused not only on safety but also evaluates the immune response of the individual to the vaccine.
Indian cancer research center (ICRC) bacilli: Another variant belonging to the M. avium intracellulare group, the ICRC bacilli are thought to induce lepromin conversion in lepromatous leprosy patients and in lepromin-negative leprosy-free individuals. Its efficacy was reported to be 65.5 percent [8].
M. vaccae: The studies with this soil-dwelling mycobacterial species combined with BCG showed to provide greater protection against leprosy, but a Vietnamese trial contradicted the results [8].
M. Habana: This bacilli has been reported to induce lepromin conversion when used as a live vaccine in monkeys, and protected mice against the development of leprosy [8].
Chemoprophylaxis alone provides two-year protective window while effective immunization will provide a much broader protective window. Thus many studies and research is going on to provide both chemoprophylaxis and immunization for immediate and short-term protection and longer-term protection respectively. This strategy could have better impact and distinct appeal in controlling and preventing leprosy. Such trials could also provide a gateway for the assessment and implementation of new emerging vaccines (Figure 7).
Figure 7.
Locations of leprosy vaccine testing.
7. Chemoprophylaxis (post-exposure prophylaxis)
Chemoprohylaxis using effective antibiotics focuses on providing protection to people at risk such as close contacts – family members, neighbors, co-workers, health care providers for lepers etc. Due to the stigma of disease the leprosy cases are found in clusters in all endemic regions, rather than being evenly dispersed over the whole area. Thus these high risk people can be identified and prophylaxis provided along with secondary prevention strategies. The process includes focused surveillance, contact tracing, early diagnosis and treatment. This helps in reducing the incidence and breaking the chain of transmission.
Chemoprophylaxis, as recommended by WHO Guideline Development Group (GDG), is done using single dose rifampicin (SDR) for contacts of leprosy patients both in adults and children of 2 years of age and above. Before starting the drug leprosy and TB disease are to be excluded. There should be no contraindications also for the use of rifampicin.
Other important considerations for the implementation of this chemoprophylaxis by programs are:
Adequate management of contacts.
Consent of the index case to disclose his/her disease.
An RCT found that SDR reduces risk of leprosy over 5–6 years in leprosy contacts. For every 1000 contacts treated with SDR, there were four leprosy cases prevented after 1–2 years and three cases prevented after 5–6 years.
Recommended dosage schedules for SDR are given in Table 1.
High bacillary load cannot be eliminated using single dose.
Specific screening test needed to distinguish between contacts with high and low bacillary load.
8. Deformity prevention and rehabilitation
Among communicable diseases, leprosy remains a leading cause of peripheral neuropathy and disability in the world, despite extensive efforts to reduce the disease burden. It is an important aspect of leprosy control. It means the medical, surgical, social, educational, and vocational restoration as far as possible of treated patients to normal activity so that they resume their place in the home, in society and industry [5, 6, 7]. Early treatment helps in disability limitation.
Rehabilitation: WHO has defined rehabilitation as “the combined and coordinated use of medical, social, educational and vocational measures for training and retraining the individual to the highest possible level of functional ability.”
Preventive rehabilitation consists of prevention of development of disabilities in a leprosy patient by early diagnosis and prompt treatment. But once the patient becomes handicapped and suffers from the damage caused, should be trained and retrained to the maximum functional ability so that the patient becomes useful to self, to the family and to community at large by various measures such as medical (physical), surgical, psychological, vocational and social rehabilitation (Flow chart 20.10).
9. Health education
Health education is given to the patient, to the family and to the community at large about leprosy. The education should be directed to ensure general public and patients help them develop their own actions and efforts to change the perception about the disease and seeking professional help whenever required. Early recognition of symptoms, prompt diagnosis, health seeking behavior, personal care, treatment adherence and rehabilitation are important aspects of health education. The key messages included are about the cause of disease and the complete cure available to encourage people for early diagnosis and treatment. It also aims at helping people to change their attitude and behavior by removing the misunderstandings and misconceptions. Mass Health education also helps to eradicate social stigma, social ostracism and social prejudice associated with leprosy which is the biggest hindrance for the eradication of disease.
10. Social and financial support
The complications of the disease cause disfigurement and disabilities which in turn gives way to the stigma and strong discrimination of these patients. This results not only in physical and social isolation also financial dependency, ultimately forcing the leprosy patients to beg on streets for their survival. To address this issue WHO introduced the strategy of community-based rehabilitation (CBR). This intended to enhance the quality of life for lepers with disabilities through community initiatives. Community participation and using local resources to support the rehabilitation of people with disabilities within their own communities is the foundation of this concept [9, 10].
11. Programmatic measures
11.1 Prevention of leprosy globally
11.1.1 The enhanced global strategy for further reducing the disease burden due to leprosy 2011–2015
“Enhanced Global Strategy for Further Reducing the Disease Burden due to Leprosy for 2011–2015” was launched in 2009 by the World Health Organization. The target of the program was to reduce Grade 2 Disability rate (G2DR) in leprosy patients by at least 35% by the end of 2015 (G2DR is the number of new cases with grade 2 disability per 100,000 population). Since the elimination of leprosy in 2005, the prevalence is very less and thus G2DR has been proposed as an indicator. The advantage of G2DR as indicator is that, it is less susceptible to operational factors such as detection delay and is a more robust marker for mapping cases of leprosy in any country. This will also help the program implementers to focus on interventions that reduce visible deformities by enhancing early detection and treatment of leprosy patients and ultimately reduce the number of new leprosy cases in the population. However by the end of 2015, only Thailand was able to achieve this target [11].
11.1.2 Global leprosy strategy 2016–2020: accelerating towards a leprosy-free world
In 2016, WHO launched the “Global Leprosy Strategy 2016–2020: Accelerating towards a leprosy-free world” [9].
The program aims to reinvigorate efforts to control leprosy and avert disabilities, especially among children still affected by the disease in endemic countries.
The strategy is built around three major pillars:
Strengthen government ownership and partnerships;
Stop leprosy and its complications; and
Stop discrimination and promote inclusion.
The strategy of this program is:
To sustain expertise and increase the number of skilled leprosy staff;
To improve the participation of affected persons in leprosy services;
To reduce visible deformities and stigma associated with the disease;
To call for renewed political commitment and enhanced coordination among partners;
To highlight the importance of research and improved data collection and analysis.
The key interventions needed to achieve these targets include:
Early case detection especially in children before visible disabilities occur thus reduce transmission;
In highly endemic areas or communities detection of disease among higher risk groups through campaigns;
Improving health care coverage and access for marginalized populations such as poor patients, patients in the difficult to reach areas and the areas of conflicts.
Customization of the strategic interventions in endemic countries is permitted to suit the national plans to meet the new targets. E.g. Screening all close contacts of persons affected by leprosy; initiating a shorter and uniform treatment regimen; and incorporating specific interventions against stigmatization and discrimination.
Its ultimate goal of this program is to further reduce the global and local leprosy burden, that is, (a) zero disabilities in children with leprosy-affected, (b) G2DR less than one per million population and (c) repeal of laws that discriminate leprosy patients of their rights.
Conflict of interest
Author declares no conflict of interest.
\n',keywords:"leprosy, prevention, vaccine, disability, multidrug therapy, rehabilitation",chapterPDFUrl:"https://cdn.intechopen.com/pdfs/72196.pdf",chapterXML:"https://mts.intechopen.com/source/xml/72196.xml",downloadPdfUrl:"/chapter/pdf-download/72196",previewPdfUrl:"/chapter/pdf-preview/72196",totalDownloads:252,totalViews:0,totalCrossrefCites:0,dateSubmitted:"April 25th 2019",dateReviewed:"March 11th 2020",datePrePublished:"May 16th 2020",datePublished:"September 9th 2020",dateFinished:null,readingETA:"0",abstract:"Hansen’s disease is one of the most ancient diseases that is still prevalent in the world. The causative agent, Mycobacterium leprae (M. leprae) has a long incubation period, clinical features after infection are identified late and these acid fast bacilli cannot be cultured – making leprosy a difficult disease to eradicate. Therefore the prevention and control of disease becomes more important. The shift of treatment from dapsone monotherapy to multidrug therapy regimen has given a new hope. The multidrug therapy coupled with the newer vaccines promise better results to prevent further transmission. Globally and locally the efforts to decrease the burden of leprosy by using different strategies has resulted in elimination of leprosy. But there is still a long way to go to make world free of this dreaded disease.",reviewType:"peer-reviewed",bibtexUrl:"/chapter/bibtex/72196",risUrl:"/chapter/ris/72196",signatures:"Vaseem Anjum",book:{id:"9138",title:"Public Health in Developing Countries",subtitle:"Challenges and Opportunities",fullTitle:"Public Health in Developing Countries - Challenges and Opportunities",slug:"public-health-in-developing-countries-challenges-and-opportunities",publishedDate:"September 9th 2020",bookSignature:"Edlyne Eze Anugwom and Niyi Awofeso",coverURL:"https://cdn.intechopen.com/books/images_new/9138.jpg",licenceType:"CC BY 3.0",editedByType:"Edited by",editors:[{id:"293469",title:null,name:"Edlyne Eze",middleName:null,surname:"Anugwom",slug:"edlyne-eze-anugwom",fullName:"Edlyne Eze Anugwom"}],productType:{id:"1",title:"Edited Volume",chapterContentType:"chapter",authoredCaption:"Edited by"}},authors:[{id:"303053",title:"M.D.",name:"Vaseem",middleName:null,surname:"Anjum",fullName:"Vaseem Anjum",slug:"vaseem-anjum",email:"vaseemanjum8@gmail.com",position:null,institution:null}],sections:[{id:"sec_1",title:"1. Introduction",level:"1"},{id:"sec_2",title:"2. Burden of disease",level:"1"},{id:"sec_3",title:"3. Control of leprosy",level:"1"},{id:"sec_4",title:"4. Medical measures",level:"1"},{id:"sec_4_2",title:"4.1 Estimation of the burden of leprosy",level:"2"},{id:"sec_5_2",title:"4.2 Early Case Detection",level:"2"},{id:"sec_6_2",title:"4.3 Chemotherapy",level:"2"},{id:"sec_8",title:"5. Surveillance",level:"1"},{id:"sec_9",title:"6. Immunoprophylaxis",level:"1"},{id:"sec_10",title:"7. Chemoprophylaxis (post-exposure prophylaxis)",level:"1"},{id:"sec_11",title:"8. Deformity prevention and rehabilitation",level:"1"},{id:"sec_12",title:"9. Health education",level:"1"},{id:"sec_13",title:"10. Social and financial support",level:"1"},{id:"sec_14",title:"11. Programmatic measures",level:"1"},{id:"sec_14_2",title:"11.1 Prevention of leprosy globally",level:"2"},{id:"sec_14_3",title:"11.1.1 The enhanced global strategy for further reducing the disease burden due to leprosy 2011–2015",level:"3"},{id:"sec_15_3",title:"11.1.2 Global leprosy strategy 2016–2020: accelerating towards a leprosy-free world",level:"3"},{id:"sec_21",title:"Conflict of interest",level:"1"}],chapterReferences:[{id:"B1",body:'World Health Organization. Global leprosy burden. Weekly Epidemiological Record. 2005;13:118-124'},{id:"B2",body:'Guide to eliminate leprosy as a Public Health Problem. Leprosy Elimination Group World Health Organisation CH-1211 Geneva 27 Switzerland. 2000. Available from: www.who.int/lep, WHO/CDS/CPE/CEE/2000.14'},{id:"B3",body:'Guidelines for the diagnosis, treatment and prevention of leprosy. New Delhi: World Health Organization, Regional Office for South-East Asia; 2017. Licence: CC BY-NC-SA 3.0 IGO'},{id:"B4",body:'World Health Organization, Department of Control of Neglected Tropical Diseases. Global leprosy update, 2017: Reducing the disease burden due to leprosy. Weekly Epidemiological Record. 2018;93(35):445-456'},{id:"B5",body:'Park K. Park Textbook of Preventive and Social Medicine. 24th ed. Banaras: Bhanott; 2014. pp. 332-347'},{id:"B6",body:'Bharadwaj R. Textbook of Public Health and Community Medicine. 1st ed. Pune: Department of Community Medicine, Armed Forces Medical College; 2009. pp. 1173-1176'},{id:"B7",body:'Suryakantha AH. Community Medicine with Recent Advances. 3rd ed. New Delhi: Jaypee Brothers Medical Publishers (P) Ltd; 2014. pp. 325-341'},{id:"B8",body:'Steven GR, Malcolm SD. The International Textbook of Leprosy, Part II, Section 6, Chapter 6.4. Vaccines for Prevention of Leprosy, Infectious Disease Research Institute; 2016'},{id:"B9",body:'World Health Organization, Regional Office for South-East Asia, Global Leprosy Programme. Global Leprosy Strategy 2016-2020: Accelerating Towards a Leprosy-Free World. New Delhi: WHO Regional Office for South-East Asia; 2016. Available from: http://apps.who.int/iris/bitstream/handle/10665/208824/9789290225096_en.pdf [Accessed: 09 July 2019]'},{id:"B10",body:'WHO/ILEP Technical Guide on Community-Based Rehabilitation and Leprosy: Meeting the Rehabilitation Needs of People Affected by Leprosy and Promoting Quality of Life. Geneva: World Health Organization; 2007'},{id:"B11",body:'Alberts CJ et al. Potential effect of the World Health Organization\'s 2011-2015 global leprosy strategy on the prevalence of grade 2 disability: A trend analysis. Bulletin of the World Health Organization. 2011;89(7):487-495. DOI: 10.2471/BLT.10.085662'}],footnotes:[],contributors:[{corresp:"yes",contributorFullName:"Vaseem Anjum",address:"vaseemanjum8@gmail.com",affiliation:'
Department of Community Medicine, Deccan College of Medical Sciences, Hyderabad, Telangana, India
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UK Research and Innovation (former Research Councils UK (RCUK) - including AHRC, BBSRC, ESRC, EPSRC, MRC, NERC, STFC.) Processing charges for books/book chapters can be covered through RCUK block grants which are allocated to most universities in the UK, which then handle the OA publication funding requests. It is at the discretion of the university whether it will approve the request.)
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