1. Introduction
α1-acid glycoprotein (AGP), also called
The biological role of AGP is not completely understood, albeit numerous
Similar to plasma albumin, the binding and transportation of a range of endogenous and exogenous compounds is one of the major physiological functions of AGP.[29] Therefore, drug binding to AGP is important in terms of the correct understanding of pharmacokinetics of drugs, especially during acute phase conditions. We have been investigating the drug-binding specificity and pharmacokinetic properties of AGP using various biophysical and biochemical analytical methods such as spectrophotometry and protein engineering for the past twenty years. Furthermore, we recently succeeded in elucidating the first structure of the AGP (variant A) and its complex with drugs.[30]
In this chapter, a brief overview of the structures of the two AGP variants, characterization of the drug-binding, pharmacokinetic properties and the biological functions of AGP are discussed.
2. Variants of AGP
AGP exists as three main genetic variants with the genes located in tandem on chromosome 9.[31] The expression of AGP is under the control of three adjacent genes; AGP-A, which encodes the F1, F2 and S variants, whereas AGP-B and AGP-B’ encode the A variant.[32] All three genes are structurally similar to each other, the AGP B/B’ genes are identical whereas the AGP A gene contains 22 codon/base substitutions.[33] The precursor product of the AGP-A gene is a 201 amino acid polypeptide with a secretory N-terminal signal peptide of 18 residues. The F1 and S variants are distributed worldwide, but the F2 variant is limited to Europeans and West Asians.[34-36] The F1, F2 and S variants are generally collectively referred as F1*S, because they are encoded by two alleles of the ORM1 gene (AGP-A) differing in less than five amino acids (F1 has Gln-38/Val-174; F2 has Gln-38/Met-174 and S has Arg-38/Val-174). On the other hand, the A variant is coded by the ORM2 gene (AGP-B/B’) with approximately 20 amino acid substitutions. The F1*S and A variants differ in their amino acid sequences by approximately 20 residues out of a total of 183 residues (Figure 1).[37]
In most individuals, the molar ratio of the F1*S and A variants in blood typically ranges from 3:1 to 2:1.[36, 38] However, the relative proportions of the products of the AGP-A and AGP-B/B’ genes have been found to change during acute phase reactions.[39, 40] Vékey and co-workers reported that the molar ratio of the F1*S and A variants was in the vicinity of 8:1 in the plasma of lymphoma, melanoma and ovarian cancer patients.[41] This means that not only the total concentration of AGP but also the molar ratio of the F1*S and A variants may be altered under certain types of pathological conditions. As mentioned in the introduction, the binding and transportation of a range of endogenous and exogenous compounds is one of the major physiological roles of AGP.[29] Furthermore, the F1*S and A variants have different drug-binding selectivity (for details, see section “4”, “drug-binding properties”).[42] Therefore, an increase in AGP concentration and a change in the ratio of the AGP (F1*S and A) variants would affect the pharmacokinetics and pharmacodynamics of drugs that are bound to AGP during inflammation and chronic disease.
3. Structure
3.1. Glycosylation
AGP has five N-linked glycans that make up more than 40% of the total mass of the molecule.[3] The N-glycosylation sites of AGP (Asn-15, -38, -54, -75, -85) can carry any one of the glycans shown in Figure 2 corresponding to different degrees of branching (bi-, tri- and tetra-antennary).[1] These glycans are structurally heterogeneous due to the great diversity of the terminating sugars. As shown in Figure 2, sialic acid is one of the common terminating sugars, and can be linked to a galactose residue
The glycosylation of AGP has been reported to change under various physiological and pathological states. [52] For example, a substantial increase in bi-antennary glycoforms as well as an increase in the degree of 3-fucosylation occurs in the early phase of an acute-phase reaction.[53] The AGP in cancer patients (lymphoma, ovarian tumor etc.) was found to have increased both sialylation and fucosylation, and different relative proportions of the total amounts of bi-, tri- and tetra-antennary sequences.[48, 54, 55] Furthermore, other pathological conditions like chronic inflammation, pregnancy, rheumatoid arthritis, alcoholic liver cirrhosis, sepsis are also known to cause changes in AGP glycosylation.[33, 56-60] Whether the changes in AGP glycosylation have any effect on the biological functions of AGP remains unknown. However, the presence of glycans has been reported to affect the conformational stability and post-translational modification of the folding process of glycoproteins, which include HIV-1 type-glycoprotein 123, quercetin 2, 3-dioxygenase, α1-antitrypsin and prion protein.[61-64] Therefore, it is highly possible that the changes in AGP glycosylation that occur under various pathological conditions may serve to either protect the AGP protein from exogenous stress or facilitate various immunomodulatory or anti-inflammation events.
3.2. Protein
Highly heterogeneous carbohydrate chains of the AGP molecule makes it difficult to reveal the 3D-structure of AGP. For structural determination by X-ray crystallography, the glycans must be removed from AGP using enzymatic methods, but these procedures fail to completely remove all of the glycan structures, due to following reasons; (i) AGP must be denatured and the disulfide bonds must be reduced to allow the enzyme to digest all glycans. (ii) AGP that is enzymatically deglycosylated is much less soluble in water, thereby resulting in uneven digestion and may create a mixture of polymerized forms. Hence, structural data cannot be obtained from enzymatically deglycosylated AGP. In 2003, Kopecky
Skerra and co-workers recently reported the first high-resolution X-ray structure of the recombinant unglycosylated F1*S variant of human AGP expressed from
4. Drug-binding properties
AGP exists in a mixture of two or three genetic variants. Herve´
Molecular docking and modeling using the crystal structures of the A and F1*S variants are an alternate route to characterizing the drug-binding properties of AGP. Skerra and co-workers modeled the mode of binding of diazepam and progesterone to the F1*S variant, and predicted that (i) the polar diazepine ring of diazepam fits into the charged lobe II, resulting in the formation of two hydrogen bounds between the carbonyl oxygen to the side chains of Glu-64 and Gln-66, and that the two ring nitrogens were in contact with Arg-90 and Tyr-127, respectively. (ii) progesterone fitted nicely into lobe I and both Tyr-127 and Ser-40 was crucial for its binding.[70] Furthermore, Azad
CD and fluorescence spectrometry is also a useful tool for examining the drug-binding sites of AGP. We found that electrostatic and hydrophobic forces have an important role in interactions between AGP and basic drugs.[79, 80] Furthermore, the results of fluorescent probe displacement experiments showed that basic drugs strongly displaced not only basic probes, but also acidic probes.[81] On the other hand, acidic probes were displaced by acidic drugs but had no effect on most of the basic probes. The results of the probe displacement study suggest that acidic drugs do not bind to an identical binding region as basic drugs, while acidic drugs do not share a binding region with basic drugs.
Photoaffinity labeling experiments and the use of chemically or genetically modified AGP can provide direct evidence for the specific amino acid residue that is involved in drug binding. The low distribution volumes of 7-hydroxystaurosporine (UCN-01), a protein kinase inhibitor anticancer drug,[82, 83] in patients was caused, in part, by its extraordinarily high affinity and specific binding (Ka = 108 M-1) to AGP.[84] Chemical modification of all His, Lys, Trp, and Tyr residues of AGP by reacting them with diethylpyrocarbonate, a phenyl isocyanate, 2-hydroxy-5-nitrobenzyl bromide, tetranitromethane, respectively, decreased the binding affinity of AGP to UCN-01.[83] In particular, Trp-modified AGP showed a significant decrease in binding. On the other hand, Zsila and Iwao used induced CD spectra and mutants of AGP to investigate its drug-binding sites, and reported that Trp25 is also involved in the binding of drugs to AGP.[85]
In addition, AGP mutants (W25A, W122A, and W160A)[86] photolabeled with [3H]-UCN-01[87] revealed that only W160A showed a marked decrease in the extent of photoincorporation. These results strongly suggest that Trp-160 and Trp-25 play an essential role in the high affinity binding of UCN-01 to AGP. Furthermore, the displacement effects of propranolol, warfarin and progesterone on UCN-01-AGP binding were competitive in nature,[88] indicating that the UCN-01 binding site on AGP is partly overlapped with the binding site for basic drugs, acidic drugs, and steroid hormones.
Another investigation based on photoaffinity labeling experiments with [3H]-flunitrazepam, also reported that [3H]-flunitrazepam photolabeled an amino acid residue within the sequence of Tyr91-Arg105.[89] In addition, Kopecky
The unexpectedly high plasma concentrations of UCN-01 after intravascular administration in a clinical study in relation to preclinical studies (mice, rats, dogs) were found to be due to the high-affinity binding of UCN-01 to human AGP.[84] Investigation of species differences in the drug-binding properties of AGP is one of the important issues for the extrapolation of drug-protein interactions from animals to humans. We previously reported that both dog and bovine AGPs contain a basic ligand binding site and a steroid hormone binding site, which significantly overlaps and affects each other, but do not contain an acid ligand binding site.[91] On the other hand, the ligand binding site on human AGP consists of at least three partially overlapping subsites: a basic ligand binding site, an acidic ligand binding site and a steroid hormone binding site. Zsila
Drugs bound to AGP have been proposed to be incorporated into cells of organs and tissues
5. Disposition
AGP is mainly biosynthesized in the liver and secreted into the blood circulation.[5, 6] In addition to the liver, other organs including the heart, stomach and lungs etc. are also able to synthesize and secrete AGP.[1] However, the disposition of endogenous AGP after being secreted into the circulation is not fully understood. In 1961, Weisman
Keyler
The glycans of AGP are known to be largely responsible for the pharmacokinetic properties of the molecule, especially the elimination of AGP. The presence of glycans has been found to contribute in preventing accelerated clearance by glomerular filtration in the kidney, because AGP is a relatively small protein of approximately 44 kDa. In order to clarify the role of glycans in the renal elimination of AGP, we prepared a recombinant glycan-deficient AGP by mutating the five Asn residues to Asp residues using a Pichia expression system and studied the pharmacokinetics of this recombinant glycan-deficient AGP in mice.[101] The glycan-deficient AGP was eliminated from the blood circulation very rapidly, due to filtration in the kidney. In addition, McCurdy
An asialoglycoprotein receptor has been reported to be associated with the incorporation of AGP into liver tissue.[102] Regoeczi
The oligosaccharide chains of AGP have different degrees of branching (bi-, tri- and tetra-antennary) that is influenced by the physiological conditions. The pharmacokinetics of AGP, in turn, is also affected by the proportion of the bi-antennary glycans. Parivar
6. Biological functions
The several fold increase of AGP concentration in the circulation during an acute phase response could influence the biological functions of the molecule in humans. [111] Although the detailed biological functions of AGP has not been elucidated completely, the major physiological roles of AGP reported so far involve the binding and transport of a range of drugs and immunomodulating effects. These physiological roles of AGP have been reviewed in section “4” and elsewhere.[1, 4] Thus, the scope of this section is limited to some interesting observations for other roles.
Van Molle
AGP has also been reported to have a protective effect against sepsis from gram-negative infections.[119] Moore
The effects of AGP on erythrocyte membranes have also been reported.[122-124] Maeda
7. Conclusions
Since the initial discovery of AGP, numerous attempts have been made to study characteristics of the molecule, but the actual roles of AGP are yet to be fully understood. Recent advances in scientific technologies such as recombinant protein engineering provide novel and sophisticated tools to further elucidating the molecular and functional aspects of AGP. Among the recent findings, high-resolution X-ray structural data for recombinant the unglycosylated F1*S and A variants of human AGP would greatly promote the development of AGP research. In the near future, it is expected that AGP, like albumin, fibrinogen and immunoglobulin, will be developed for use in a variety of clinical situations.
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