Non-enzymatic glycation mediated structure–function changes in proteins: case of serum albumin

Abstract

Albumin, a major plasma protein with extraordinary ligand binding properties, transports various ligands ranging from drugs, hormones, fatty acids, and toxins to different tissues and organs in the body. Albumin can undergo glycation on reacting with circulating reducing sugars, and this modification can occur even more frequently under hyperglycaemic conditions. Glycation is a non-enzymatic reaction of proteins and sugars, which gives rise to the formation of early and advanced glycation end products (AGEs). AGEs are a fundamental factor in the development and progression of severe diabetic complications such as nephropathy, neuropathy, retinopathy and cardiovascular disorders. The pathological impact of AGEs is mainly attributed to the structural modifications of proteins due to their cross-linking properties and the modification of lysine and arginine side chains. Herein, we review the structure–function effects of glycation on albumin, specifically focusing on its drug binding functions. Considering its physiological significance, there is a need to focus current research on determining the structure–function impacts of non-enzymatic glycation on serum albumin.

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Introduction

Despite the efforts that have been made towards understanding and managing diabetes, this metabolic disorder and its complications are increasing unabated.^1–3 Blood glucose levels are regulated by various factors affecting the digestion and absorption of dietary carbohydrates, hepatic glucose control, and the storage, production, and efficiency of insulin to stimulate glucose uptake.⁴ Considering the number of deaths associated with hyperglycaemia, there is a need to develop a utile approach for the prevention of diabetes as well as to understand its underlying pathophysiology.^5,6 Improvements in lifestyle involving a healthy diet, weight loss and increased physical activity have been observed to have long lasting effects in the prevention of type 2 diabetes.^7–9 In addition to being the leading cause of disease-related deaths, excessive sugar levels in diabetes could also accelerate the process of non-enzymatic glycation of various body proteins, nucleic acids and lipids.^10,11

Glycation of proteins has been identified as a key player in the development of various complications in diabetes, such as neuropathy,^12–15 nephropathy,^16–20 retinopathy,^21–24 and cardiovascular disorders.^18,25–27 Due to the complexity and the physiological impact of glycation, for several decades, current diabetes research has focused on determining the physiological role of glycation end products (AGEs) and their biological effects. Louis Camille Maillard (1878–1936) first demonstrated the sugar amino acid reaction on heating. He proposed that the browning reaction involved the formation of an intermediate Schiff base intermediate; later, this reaction was named the “Maillard reaction”. Non-enzymatic glycation occurs even under normal conditions over the course of a lifetime, and accumulation of advanced glycation end products (AGEs) has been proposed to be the hallmark of the aging process.²⁸ Glycation is a multistep, slow reaction between free amino groups in proteins and reducing sugars, as shown in Fig. 1. The glycation reaction leads to the formation of heterogeneous AGEs involving complex reactions such as oxidation, dehydration, and cyclization. Reducing sugars react with free amino groups in proteins to form a Schiff base which undergoes structural changes to form the Amadori product.^29,30 Glyoxal, a product of glucose autoxidation, could react with proteins to form CML and GOLD, whereas methylglyoxal, which is a breakdown product of the Amadori product, can give rise to the formation of imidazolium cross links and MOLD. Glyoxallic acid, glyoxal and methylglyoxal are considered to be AGE intermediates because they can give rise to the formation of AGEs through glucose protein reactions. Since the discovery of the glycation reaction, extensive research has been carried out to analyse the properties of advanced glycation end products (AGEs). AGEs have been classified based on their fluorescence and cross-linking properties.^31–33 The chemical process of glycation is sensitive to pH, temperature, hydration, the type of sugar, and buffer conditions.³⁴

Fig. 1 Schematic of non-enzymatic glycation reactions and the formation of advanced glycation end products (AGEs).

Fig. 2 shows the structures of different sugars (glucose, fructose, ribose, etc.) as well as early (fructosamine), intermediate (glyoxal, methylglyoxal, 3-deoxygluconosone, 3-deoxygluconosone, etc.) and advanced glycation end products. Most of the AGEs identified to date are derivatives of either lysine or arginine. AGEs have also been found to form cross-links between two lysine residues or between a lysine and an arginine residue.^35,36 Hyperglycaemic conditions, where blood glucose increases above normal levels, are known to result in an increased flux of glucose and its metabolic intermediates towards different pathways, contributing to the formation of highly toxic pro-oxidants called AGEs.^37,38 The excess glucose present under hyperglycaemic conditions can enter the polyol pathway and can lead to increased accumulation of di-carbonyl compounds.³⁹ Fig. 3 shows the different pathways involved in the formation and accumulation of AGEs.^31,37,40 It has been observed that the metabolic intermediates of glucose exhibit comparatively higher reactivity with free amino groups in proteins than glucose itself.⁴¹ Glyoxyllic acid (GA), pyruvic acid (PA) and methylglyoxal (MG) are examples of the metabolic intermediates of glucose formed through different pathways.⁴² Methylglyoxal is a highly reactive oxaldehyde formed in vivo by the glycolytic pathway. Methylglyoxal leads to the modification of arginine residues, resulting in the formation of highly toxic fluorescent AGEs, i.e. argpyrimidine (Arg-P).^43,44 Among the various heterogeneous AGEs analyzed to date and shown in Fig. 2, carboxymethyllysine (CML), carboxyethyllysine (CEL), argpyrimidine (Arg-P) and pentosidine have been observed to be the most predominant AGEs formed in the body under pathological conditions.^43,45–49

Fig. 2 The structures of different sugars and early, intermediate and advanced glycation end products.

Fig. 3 Schematic of the different pathways involved in the formation and accumulation of AGEs.

Role of AGEs in diabetic complications

The current focus of diabetes research is moving away from the control of acute metabolic imbalances and towards the prevention of chronic complications such as neuropathy, nephropathy, retinopathy and cardiovascular complications. Non-enzymatic glycation and AGE accumulation have been proposed to be the main causes of the pathogenesis of these severe diabetic complications. AGEs are pro-oxidants with high reactivities and cross-linking properties, and they can activate a cascade of inflammatory pathways upon interaction with receptors to generate advanced glycation end products (RAGE).^50–53

Diabetic retinopathy

Diabetic retinopathy results in poor vision or complete vision loss.⁵⁴ Glycation and AGEs play key roles in the pathogenesis of retinopathy. Diabetic cataract, characterized by opacification of the lens, can also eventually result in vision loss. Non-enzymatic glycation of lens crystalline has been found to cause conformational changes leading to cross-linking and aggregation.^55–57 The formation of AGEs and the accumulation of glycated crystalline aggregates have been found to be responsible for opacification, as determined from both in vitro and in vivo studies.^58–61

Neurological disorders

The accumulation of AGEs under hyperglycaemic conditions has been linked with the development of diabetic neuropathy.⁶² Glycated myelin has been found to be more susceptible to the activation of macrophages and phagocytosis, which could lead to demyelination.⁶³ The activation of the polyol pathway and the development of oxidative stress have been proposed to be the factors responsible for the pathogenesis of diabetic neuropathy.^14,64 Glycation induces amyloid aggregation of proteins⁶⁵ and also enhances the neuronal toxicity of β-amyloid aggregates.⁶⁶ The role of AGEs in the progression of neurological disorders such as Alzheimer's disease⁶⁷ and in the development of diabetic neuropathy have been well established. AGE-mediated toxicity can result in the development of pathological conditions such as Alzheimer's disease and Parkinson's disease.^68,69

Micro and macro vascular complications

Both early glycation and AGEs are known to be responsible for the development and progression of vascular complications in diabetes patients.^70–72 AGEs accumulation results in the development of cardiovascular complications, mainly due to structure–function modification and impairment of the mechanical properties of tissues through cross-linking of matrix proteins.⁷³ AGEs can modulate cellular processes by interacting with cell surface receptors (receptors for AGEs, i.e. RAGE) and activating inflammatory pathways.^50–53

Diabetic nephropathy

AGEs exhibit inflammatory and fibrotic effects on retinal tubular epithelial cells and are involved in the development of diabetic nephropathy.^74,75 AGE accumulation can cause damage to the peritoneum and result in the loss of ultrafiltration capacity.⁷⁶ Elevated levels of AGEs in the plasma, amyloid fibrils and skin of haemodialysis patients have been shown in recent studies.⁷⁷ AGEs have been implicated in the progression of chronic kidney disease (CKD), specifically in diabetic nephropathy.⁷⁸

Other complications

Non-enzymatic glycation and accumulation of AGEs is also involved in the progression and development of diabetic atherosclerosis,^79,80 skin aging,⁸¹ liver disease,⁸² etc. It was found that AGEs enhance proliferation, migration and invasion of breast cancer cell lines.⁸³ Also, it has been proposed that mitochondrial glycation could contribute to the development of diabetes, ageing, cancer, and neurodegeneration.⁸⁴

Non-enzymatic glycation of proteins in vivo

Under both normal and hyperglycaemic conditions, many proteins have been found to be greatly affected by non-enzymatic glycation.^85,86 In addition to the N-terminal amino group, proteins also contain a large number of lysine and arginine residues with side chains containing free amino groups. Proteins which have been reported to be modified due to non-enzymatic glycation include serum proteins, membrane proteins, enzymes and both intra- and extracellular structural proteins. Fig. 4 shows a schematic of proteins that are modified by glycation. Glycation leads to cross-linking of proteins, resulting in loss of their functions. Glycation-mediated cross-linking of collagen has been observed to be a key factor in skin aging.^81,87 Non-enzymatic glycation of red blood cell (RBC) membrane proteins has been observed in diabetes.⁸⁸ Glycation of insulin has been found to result in the impairment of its ability to regulate blood glucose.⁸⁹ The restrained allosteric transition in hemoglobin due to glycation results in loss of its oxygen-carrying function and development of oxidative stress.⁹⁰ Glycation of the milk protein casein has been shown to induce its oligomerization and affect its functional properties.⁹¹

Fig. 4 Different proteins modified by glycation.

The micro-heterogeneity and non-specificity of non-enzymatic glycation are major limitations in structural studies of glycated proteins using X-ray crystallography or nuclear magnetic resonance (NMR). A large number of structural studies of glycated proteins are limited to the study of secondary structural changes using circular dichroism. With the advent of mass spectroscopic analysis, new approaches have been proposed towards the quantitative analysis of glycation adducts and the identification of types of AGEs.^92–96 The heterogeneity associated with non-enzymatic glycation has added to the complexity of the problem and has limited the possibilities of exploring the crystal structures of modified proteins.

Structure of albumin

Albumins are globular proteins with high water solubility; they are mainly involved in transport. The structure of serum albumin has been extensively studied based on X-ray crystallography, and it has been shown to exhibit a heart shape in its three-dimensional form. The molecular weight of serum albumin is 66.5 kDa. It is a single chain protein consisting of 585 residues. The three-dimensional crystal structure of serum albumin is shown in Fig. 5. The structure of albumin is broadly divided into three domains (I, II, III), each of which is further divided into two subdomains, A and B. The native structure of albumin is predominantly helical.^97–101 Albumin contains 35 cysteine residues; 34 of them form disulfides and stabilize the structure. Also, human serum albumin contains only a single tryptophan residue (Trp-214), whereas its bovine homologue contains two tryptophan residues (Trp134 and Trp213).¹⁰² The fluorescence behaviour of these tryptophan residues has been extensively used to study ligand interactions and the structural changes in albumin.

Fig. 5 Three-dimensional structure of serum albumin and its ligand binding sites.

Albumin contains seven fatty acid binding sites¹⁰³ (represented by spheres in Fig. 5) and two major drug binding sites, named Sudlow's site I and II.^104–106 The bovine homologue of human serum albumin has been extensively used due to its high sequence similarity, low cost and high availability to understand the structure–functional changes upon ligand binding and the mechanisms of carrier functions.^107,108 Due to its extraordinary ligand binding properties for a broad range of small molecules, such as fatty acids, bilirubin, thyroxine, bile acids and steroid hormones, albumin serves as a transporter for these compounds in the body.^109–111

Multiple functions of albumin

In addition to its carrier function in the body, serum albumin performs multiple physiological functions.^112–114 Albumin forms a major part of the soluble protein constituent in blood, where it performs various functions, such as a carrier for drugs, hormones, ions, bilirubin, etc.^{110,115–117} Due to its high solubility and high plasma concentration, albumin also plays a protective role for blood cells by maintaining osmotic pressure.¹¹⁸ The multiple functions performed by serum albumin are shown in Fig. 6. Due to its very good ligand binding properties, albumin is of great importance in the pharmacokinetics of many vital drugs.^{110,119–121} The two major drug-binding regions in albumin interact with a wide range of drugs for various pathological conditions. The three-dimensional structure of albumin is very well studied; its drug-binding sites have been characterized and confirmed based on co-crystallization studies using X-ray crystallography.^{102,103,106,122–124} A new, third drug site has been reported to be located in the IB subdomain of albumin.¹²⁵

Fig. 6 Multiple functions of albumin.

Albumin also serves as a major fatty acid carrier of the body, with seven fatty acid binding sites. Curry et al. (1998),¹⁰³ using an X-ray crystallographic approach, revealed the asymmetric distribution of fatty acid binding sites in albumin. Different studies have also evaluated the binding affinity of various hormones to albumin. Watanabe et al.¹²⁶ determined the affinity of BSA for six steroid hormones, i.e. alpha-estradiol, ethynylestradiol, progesterone, androsterone, dehydroisoandrosterone and testosterone; they concluded that BSA accelerates the transport of hormones. Albumin also serves a carrier for thyroxin, which is an important thyroid hormone.^123,127,128 Albumin plays a crucial role as a physiological transporter of the metal ions Cu²⁺ and Zn²⁺ in the bloodstream. Albumin also exhibits affinity for Ni²⁺, Co²⁺, and Cd²⁺ in vivo, which is of toxicological importance.¹²⁹ It binds with calcium in a pH-dependent manner, and its affinity increases with increasing pH due to electrostatic effects.¹³⁰

Recently, many studies have been carried out to determine the interaction of albumin with a wide range of ligands, ranging from drugs to natural phytochemicals from plants.^{109,131–144} In addition to its role as a drug carrier, albumin exhibits esterase activity; extensive studies have been carried out to determine the enzymatic properties of albumin.^145–151 Based on site-directed mutagenesis studies, Arg410 and Tyr411 have been shown to be the key residues responsible for the esterase activity of albumin.^152,153

Glycation of albumin

Because it is the major plasma protein, and also because it contains many lysine and arginine residues, albumin is highly prone to non-enzymatic glycation.¹⁵⁴ Different studies have identified lysine residues in albumin to be the most frequently glycated residues based on both in vitro and in vivo analysis. All the lysine and arginine residues in albumin are shown in Fig. 7. Among the 59 lysine residues, 34 have been reported to be glycated in different studies based on mass spectroscopic analysis.^{149,155–160} In addition to lysine residues, there are 24 arginine residues in albumin, which can also give rise to the formation of AGEs and cross-links on glycation.

Fig. 7 All the lysine and arginine residues in albumin.

Hyperglycaemic conditions resulting in excessive blood sugar levels and the high plasma concentration of albumin also make it highly susceptible to glycation.^161,162 Prolonged exposure to glucose under hyperglycaemic conditions is known to worsen the situation by accelerating the process of non-enzymatic glycation, leading to excessive formation of highly reactive intermediates of AGEs.

In spite of recent continuous efforts, information about the structural and functional impacts of specific AGEs on various proteins remains poorly understood. Glycation-induced structural modifications in albumin can impact its functions.¹⁶³ Because albumin is the major drug carrier of the body, the glycation of albumin can largely impact the pharmacokinetics and pharmacodynamics of many drugs and other ligands that interact with albumin.^164,165 Arginine and lysine residues are the most common glycation sites in albumin both in vivo and in vitro. The major drug binding sites in albumin are located in subdomain II A (Sudlow's site I), subdomain III A (Sudlow's site II) and the newly studied subdomain IB. The seven fatty acid binding sites located in three different domains of albumin make it a major depot for fatty acids and hormones in the body.

Site I in albumin is the preferred binding site for anionic heterocyclic drugs, whereas site II is preferentially occupied by ligands having aromatic carboxylate groups with extended conformations.^{125,166–168} Recently, a number of studies have been carried out using both HSA and BSA to determine the impact of glycation on the structure and ligand binding properties of albumin;^{163,169–174} however, the impact of individual AGEs remains undefined.

Glycation-mediated conformational transitions in albumin can eventually influence its ligand binding properties.¹⁷⁵ Glycated albumin has been extensively characterized by gel electrophoresis and by UV-Vis, fluorescence and infrared spectroscopy. Glycation does not occur in a site-specific manner and results in heterogeneous end products with varying extents of modification, types of modification (AGEs) and sites of modification.

Structural changes in albumin upon glycation

The high heterogeneity associated with glycation has limited structural studies of glycated proteins; to date, there is only one crystal structure of a glycated protein i.e. glycated hemoglobin (3B75)¹⁷⁶ in the Protein Data Bank (PDB). Other biophysical methods, such as circular dichroism (CD),¹⁷⁷ differential scanning colorimetry,¹⁷⁸ fluorescence,¹⁶⁹ and scanning and transmission electron microscopy (SEM and TEM),⁶⁵ have been mainly used to study the effect of glycation on proteins. Based on CD studies, it is well established that glycation induces structural changes in albumin, specifically resulting in increased beta sheet content.^{173,179–181} Also, it is evident from studies using both in vitro and in vivo glycation models that glycation is associated with significant structural changes.¹⁶³

In particular, the conformational changes in albumin have been probed based on tryptophan fluorescence, which is directly affected by glycation.¹⁸² Human serum albumin contains only one tryptophan residue (i.e. Trp-214), located in domain II, whereas its bovine analogue contains two tryptophan residues, i.e. Trp-134 and Trp213. It has been shown in several studies that glycation results in the quenching of tryptophan fluorescence compared to the native conformation, suggesting changes in the microenvironment of these residues.^170,183 Based on in vitro experiments, it has been shown that unfolding due to glycation results in opening of the hydrophobic regions of albumin during prolonged glycation.^173,183

In a comparative study, Guerin-Dubourg et al.¹⁸⁴ determined the structure–function changes in glucose and methylglyoxal-modified albumin with methylglyoxal using in vivo glycated albumin purified from diabetic patients. Enhanced oxidative modification was observed in the cases of both in vitro and in vivo glycated albumin. They also determined the differences in the structural and functional features of in vivo albumin compared to the in vitro models. Chesne et al.¹⁸⁵ reported oxidative modifications of albumin using pathophysiological concentrations of glucose. Based on the amounts of free energy change and unfolding, it was demonstrated that glucose induces fine structural changes in human serum albumin; it was also suggested that 175 mg dL⁻¹ glucose concentration is a critical point for structure and function alteration in albumin.¹⁸⁶ The changes in helicity, AGE fluorescence, lysine modification, surface tension value and formation of Amadori products were observed to be similar in both in vitro and in vivo conditions. Also, it was noticed that arginine modification by glucose occurred only in vivo; it was not observed under in vitro conditions.¹⁸⁷ The observed difference was proposed to be due to the presence of a glucose-derived di-carbonyl compound under physiological conditions.

Glycation induced aggregation and fibrillation

Glycated albumin has been observed to form fibrillar or amorphous aggregates with high affinity to amyloid specific dyes such as Congo red (CR) and Thioflavin T (ThT). In contrast to the native helical structure of albumin, its glycated form contains residues in β-sheeted conformations, as observed with circular dichroism spectropolarimetry. From X-ray fiber diffraction studies, the glycated form of albumin was found to exhibit a cross-β structure. Based on these findings, it was concluded that glycation can induce refolding of native helical albumin into amyloid fibrils comprising cross-β structures.⁶⁵ In 2004, Obrenovich and Monnier¹⁷⁹ reported a finding from the Dutch group of Gebbink and colleagues which showed that the posttranslational process of non-enzymatic glycation is a key mechanism in amyloid formation. It was shown that glycation induces a conformational transition in albumin from the native helical conformation to the cross-beta conformation. Based on these observations, they also proposed glycation as a predisposing factor for amyloidosis.

Based on a study to determine the effects of temperature on the aggregation of albumin using FTIR spectroscopy along with polyacrylamide gel electrophoresis (PAGE), it was concluded that glycation also plays a role in protein aggregation.¹⁸⁸ Rondeau et al.¹⁸³ further studied the thermal aggregation process of glycated albumin at different glucose concentrations; they found that glycation alters the native structure of BSA. They showed that the partial unfolding of the tertiary structure was similar in the case of both native and glycated BSA, and the aggregation was found to be progressively restrained with increasing glucose concentration. Ribosylation of BSA also has been reported to induce rapid misfolding and form globular amyloid-like aggregates with high cytotoxicity to neural cells.¹⁸⁹ In another study, fructosylation of HSA was shown to result in the generation of neo-epitopes. Also, it was observed that fructosylation resulted in protein aggregation based on gel electrophoresis.¹⁹⁰ The prolonged glycation of human serum albumin (HSA) results in significant structural changes, and 20 days of incubation with sugars induces significant amyloid fibril formation. It was proposed that prolonged glycation of HSA is associated with a conformational transition from the native helical structure to a beta-sheeted amyloid form.¹⁹¹

Glycation is known to differentially modulate the structure and function of proteins.^164,192 The structural impact of glycation has been found to differ with respect to the type of sugar, the extent of modification, the type of AGEs, buffer conditions, temperature, pH, type of protein, etc. The residues involved in the glycation mainly determine the functional impact of glycation on proteins.

Effect of glycation on albumin functions

Effect on drug transport function

Albumin is the major drug carrier in the body. In addition to drugs, albumin also interacts with various ligands such as flavonoids,^{125,193–195} dyes and pigments,^196–198 synthetic compounds, ions, and many other bioactive phytochemicals.^142,199,200 Extensive studies have been carried out, including both in vitro drug binding studies using absorbance or fluorescence-based methods, isothermal calorimetry (ITC), and X-ray crystallography in order to determine the binding sites of many drugs in albumin. Fig. 8 presents an overview of the overall impact of glycation on the structure and function of albumin.

Fig. 8 The overall impact of glycation on albumin.

Glycation is known to induce conformational changes in albumin which can affect its functions, mainly its drug binding properties. The binding affinity of HSA has been reported to decrease due to conformational changes or steric hindrance upon non-enzymatic glycation.²⁰¹ Significant impairments in the binding affinity of albumin have been observed using both in vitro and in vivo glycated albumin based on estimations of dissociation constant values and free drug fractions. Loss of drug interaction has been observed in the case of both glycated albumin purified from diabetic patients and that obtained from in vitro glycation.²⁰²

The two major drug-binding regions in albumin interact with a wide range of drugs for various pathological conditions. The three-dimensional structure of albumin is very well studied, and its ligand-binding sites have been confirmed based on co-crystallization studies using X-ray crystallography.^{102,103,106,122,124,128} A third drug site has been newly reported to be located in the subdomain IB of albumin.¹²⁵ Based on studies using methylglyoxal (MGO) modified albumin, it was found that glycation involved the arginine residues responsible for the ligand binding and enzyme activity (esterase) of albumin. Furthermore, simulation and molecular modelling results suggested that hydroimidazolone formation upon MGO modification caused structural changes that resulted in the disruption of arginine-mediated h-bonding and loss of electrostatic contacts.¹⁴⁹ The clinical relevance and the pathophysiologic importance of non-enzymatic glycation of albumin in diabetes, where glycation occurs at an accelerated rate, and the development of diabetic complications have been extensively reviewed by Cohen (2013).²⁰³

In our work on structural changes mediated by the functional impact of specific AGE modifications on BSA, we demonstrated changes in the drug-binding properties of albumin upon specific AGE modifications.¹⁶⁴ It was evident that glycation results in asymmetric conformational changes in BSA, leading to drug binding sites with reduced pocket volumes, depths and accessible surface areas. The Arg-P modification of arginine and the CEL modification of lysine residues in drug sites I and II resulted in comparatively shallow binding pockets. AGE-modified albumin exhibited lower affinities for drugs in both sites I and II.

Based on the crystal structures of HSA complex with glucose or fructose, Wang et al.²⁰⁴ showed that glucose covalently binds with Lys195 and Lys199 in its linear forms. Glucose was found to be covalently bonded to Lys195; however, this was not seen in the case of fructose, which bound in cyclic form. From the crystal structure observations, they proposed a ring opening mechanism for glucose involving Lys-195 and Lys-199 residues. Because Lys195 and Lys199 lie at the entrance of drug site I in albumin, their glycation can affect the interaction of drugs and can result in steric hindrance of drug binding.

The molecular interaction of different antibiotics with albumin showed that the capacity of antibiotics to interact with albumin is mainly determined by their chemical structures. Changes in the pharmacokinetics of teicoplanin, an antibiotic drug used against gram-positive bacteria, were observed in patients with hyperglycaemic hypoalbuminaemia. The patients showed comparatively lower serum levels of drugs following drug administration, and non-enzymatic glycation of albumin under hyperglycaemic conditions was proposed to be responsible for the poor affinity of albumin for teicoplanin.²⁰⁵

Effects on fatty acid carrier function

Albumin with seven fatty acid binding sites facilitates the uptake of fatty acids by organs in need of these substrates.^206,207 The structural changes upon glycation could affect the fatty acid carrier functions of albumin. It was observed that glycation of albumin impairs fatty acid affinity, which results in enhanced arachidonate oxygenation and also hyper-activation of platelets, as seen in type 2 diabetes patients.²⁰⁸ The impaired lipid binding properties also affect the fatty acid carrier function of albumin to required locations.²⁰⁹

Changes in the affinities of glycated albumin toward fatty acids such as linoleic acid, oleic acid, caproic acid, and lauric acid were investigated based on kinetic studies. Significant decreases were observed in the binding affinities of linoleic acid (84%), oleic acid (84%), caproic acid (90%), and lauric acid (87%). The decrease was found to be in correlation with the extent of lysine modification in glycated albumin; this also suggested that albumin loses its fatty acid binding ability due to the glycation of lysine residues involved in fatty acid binding.²¹⁰

Effects on antioxidant function

Changes in the antioxidant and radical scavenging properties of albumin have been observed both in patients with diabetes and using in vitro glycation models. In an in vitro study using BSA, it was observed that glycation results in impairment of the antioxidant functions of albumin. The conformational changes in albumin were found to be in good agreement with the loss of its antioxidant function. Based on studies with in vivo glycated albumin, poor glycemic control and non-enzymatic glycation in diabetic patients were proposed to be responsible for the loss of the antioxidant function of albumin.²¹¹ In another study with methylglyoxal modified albumin, it was suggested that the deleterious effects induced by carbonyl stress in the case of diabetic patients could also be due to impairment of the antioxidant capacity of albumin upon di-carbonyl modification.²¹² In addition to this, Faure et al. also compared the antioxidant properties and structural changes in albumin purified from patients with diabetes treated with metformin or sulfonylurease and in healthy subjects. In case of patients treated with metformin and sulfonylurease, both the oxidative stress and non-enzymatic glycation were found to be significantly lower in patients treated with metformin. They suggested that a decrease in the antioxidant capacity of albumin in patients with diabetes could lead to oxidative stress development, resulting in vascular and metabolic complications.

Glycated albumin with impaired antioxidant functions has been shown to enhance LDL oxidation, mainly by the formation of superoxide radicals. Also, BSA modified by conjugating carboxyl groups with p-aminophenyl α-D-glucopyranoside was found to exhibit membrane-perturbing activities.²¹³

Effects on esterase function of albumin

Glycation-induced conformational transitions could also affect the enzymatic properties of albumin. Studies using single and double recombinant mutants of HSA suggested that the consequences of non-enzymatic glycation on albumin can be partially explained based on the blockage of the positive charges of lysine residues at Lys199, Lys439 and Lys525. Also, the decrease in the esterase activity of modified albumin was proposed to be due to conformational changes resulting in an increased distance between Arg-410 and Tyr-411, the two residues responsible for the enzyme activity of albumin.^165,171,214 In a recent report, a dose-dependent decrease in the esterase activity of albumin was found with respect to the levels of glycation and protein aggregation.

Interaction of phytochemicals with albumin

A decrease in the binding affinity was also observed for various phytochemicals, such as quercetin, rutin, fisetin, morin and genistein, based on a multi-spectroscopic approach with glycated human serum albumin (HSA). When compared to other polyphenols, the maximum decrease in affinity was observed for quercetin.²¹⁵ It has been also proposed that non-enzymatic glycation of albumin could result in impaired binding affinities for dietary polyphenols and phenolic acids.²¹⁶ Also, in our attempt to determine the effects of methylglyoxal modification of albumin on sinigrin interaction, we observed that MGO-modified BSA showed comparatively lower affinity than native BSA.¹⁴²

Effects of glycated albumin on cells

Amadori adducts in glycated albumin have been found to be responsible for the development of diabetic nephropathy.^217,218 AGE-modified albumin has been shown to exhibit eryptotic properties on RBCs and is suggested to be responsible for the occurrence of abnormal morphologies in pathological conditions such as diabetes and chronic kidney disease.²¹⁹ Glycated albumin has been found to stimulate smooth muscle cell growth and migration. Also, it was proposed that glycated albumin may play a role in the development of diabetic atherogenesis.^220,221 Amadori adducts have been found to increase nitric oxide (NO) synthase activity in endothelial cells.²²² Also, it was observed that Amadori adducts modulate NO synthase activity; also, these effects of glycated albumin were found to be fundamental in the development of diabetic nephropathy.²²³

Structural perturbation upon Amadori modification of lysine residues has been found to be responsible for the overall immunogenicity of a glycated serum protein; this may lead to the recognition of Amadori-glycated proteins by serum autoantibodies in diabetes patients.^224–226

Conclusion

Despite the discovery of the Maillard reaction by Louis Camille Maillard in 1912, research in the area of glycation has been limited. With increasing research and the advent of new techniques such as mass spectrometry, there is increasing interest in this area. Despite the complexities of glycation and heterogeneity in the products of glycation reactions, extensive research has been performed in this area in the past two decades. The crystal structure of glycated hemoglobin, solved by our group, and glucose and fructose-linked structures of human serum albumin are the only three dimensional structures of glycated proteins determined using X-ray crystallography to date. The multifunctional albumin is a very important protein due to its physiological role in the transport of various drugs, hormones, and metal ions, maintenance of oncotic pressure, esterase activity and antioxidant functions. Due to its short half-life and high exposure to blood glucose fluctuations, glycated albumin has also been suggested to be a better marker of the glycemic index in diabetic patients. Non-enzymatic glycation of albumin affects its structure and functions, and there is a need to adopt an alternative approach to improve the efficacy of drugs in patients with hyperglycaemic conditions, where glycation occurs at an accelerated rate. Furthermore, future studies in clinical and pathophysiological scenarios will enhance our understanding of the glycation of proteins and its structure–function impacts.

Acknowledgements

The authors thank SASTRA University for providing the infrastructure to carry out the research and to the Department of Biotechnology, India for a research grant (102/IFD/SAN/1524/2016-2017).

References

1. N. Unwin, J. Shaw, P. Zimmet and K. G. Alberti, Diabetic Med., 2002, 19, 708–723.
2. A. Accurso, R. K. Bernstein, A. Dahlqvist, B. Draznin, R. D. Feinman, E. J. Fine, A. Gleed, D. B. Jacobs, G. Larson, R. H. Lustig, A. H. Manninen, S. I. McFarlane, K. Morrison, J. V. Nielsen, U. Ravnskov, K. S. Roth, R. Silvestre, J. R. Sowers, R. Sundberg, J. S. Volek, E. C. Westman, R. J. Wood, J. Wortman and M. C. Vernon, Nutr. Metab., 2008, 5, 9.
3. T. Tuomi, N. Santoro, S. Caprio, M. Cai, J. Weng and L. Groop, Lancet, 2013, 383, 1084–1094.
4. P. Zimmet, K. G. Alberti and J. Shaw, Nature, 2001, 414, 782–787.
5. R. G. McCoy, H. K. Van Houten, J. Y. Ziegenfuss, N. D. Shah, R. A. Wermers and S. A. Smith, Diabetes Care, 2012, 35, 1897–1901.
6. D. K. Tobias, A. Pan, C. L. Jackson, E. J. O'Reilly, E. L. Ding, W. C. Willett, J. E. Manson and F. B. Hu, N. Engl. J. Med., 2014, 370, 233–244.
7. F. B. Hu, J. E. Manson, M. J. Stampfer, G. Colditz, S. Liu, C. G. Solomon and W. C. Willett, N. Engl. J. Med., 2001, 345, 790–797.
8. J. Tuomilehto, J. Lindstrom, J. G. Eriksson, T. T. Valle, H. Hamalainen, P. Ilanne-Parikka, S. Keinanen-Kiukaanniemi, M. Laakso, A. Louheranta, M. Rastas, V. Salminen and M. Uusitupa, N. Engl. J. Med., 2001, 344, 1343–1350.
9. J. Lindstrom, M. Peltonen, J. G. Eriksson, P. Ilanne-Parikka, S. Aunola, S. Keinanen-Kiukaanniemi, M. Uusitupa and J. Tuomilehto, Diabetologia, 2013, 56, 284–293.
10. D. Daneman, Diabetes Care, 2001, 24, 801–802.
11. H. Vlassara and M. R. Palace, J. Intern. Med., 2002, 251, 87–101.
12. P. J. Thornalley, in International Review of Neurobiology, Academic Press, 2002, vol. 50, pp. 37–57.
13. I. Misur, K. Zarkovic, A. Barada, L. Batelja, Z. Milicevic and Z. Turk, Acta Diabetol., 2004, 41, 158–166.
14. R. Wada and S. Yagihashi, Ann. N. Y. Acad. Sci., 2005, 598–604.
15. K. Sugimoto, M. Yasujima and S. Yagihashi, Curr. Pharm. Des., 2008, 14, 953–961.
16. J. M. Forbes and M. E. Cooper, Amino Acids, 2012, 42, 1185–1192.
17. M. Lassila, K. K. Seah, T. J. Allen, V. Thallas, M. C. Thomas, R. Candido, W. C. Burns, J. M. Forbes, A. C. Calkin, M. E. Cooper and K. A. Jandeleit-Dahm, J. Am. Soc. Nephrol., 2004, 15, 2125–2138.
18. S. Yamagishi, S. Maeda, T. Matsui, S. Ueda, K. Fukami and S. Okuda, Biochim. Biophys. Acta, 2012, 5, 663–671.
19. J. M. Forbes and M. E. Cooper, Amino Acids, 2010, 42, 1185–1192.
20. P. J. Beisswenger, S. K. Howell, G. B. Russell, M. E. Miller, S. S. Rich and M. Mauer, Diabetes Care, 2013, 36, 3234–3239.
21. A. W. Stitt, Exp. Mol. Pathol., 2003, 75, 95–108.
22. Y. Sharma, S. Saxena, A. Mishra, A. Saxena and S. M. Natu, Journal of Ocular Biology, Diseases, and Informatics, 2012, 5, 63–69.
23. M. Chen, T. M. Curtis and A. W. Stitt, Curr. Med. Chem., 2013, 20, 3234–3240.
24. R. Milne and S. Brownstein, Amino Acids, 2013, 44, 1397–1407.
25. S.-i. Yamagishi, K. Nakamura and T. Imaizumi, Curr. Diabetes Rev., 2005, 1, 93–106.
26. M. Peppa and S. A. Raptis, Curr. Diabetes Rev., 2008, 4, 92–100.
27. Z. Hegab, S. Gibbons, L. Neyses and M. A. Mamas, World J. Cardiol., 2012, 4, 90–102.
28. O. Nedic, S. I. Rattan, T. Grune and I. P. Trougakos, Free Radical Res., 2013, 1, 28–38.
29. K. Sztanke and K. Pasternak, Ann. Univ. Mariae Curie-Sklodowska, Sect. D, 2003, 58, 159–162.
30. F. J. Tessier, Pathol. Biol., 2010, 58, 214–219.
31. R. Singh, A. Barden, T. Mori and L. Beilin, Diabetologia, 2001, 44, 129–146.
32. M. Peppa, J. Uribarri and H. Vlassara, Clin. Diabetes, 2003, 21, 186–187.
33. N. Ahmed, Diabetes Res. Clin. Pract., 2005, 67, 3–21.
34. H. Vlassara and G. E. Striker, Nat. Rev. Endocrinol., 2011, 7, 526–539.
35. K. M. Biemel, O. Reihl, J. Conrad and M. O. Lederer, J. Biol. Chem., 2001, 276, 23405–23412.
36. P. T. B. Bullock, D. G. Reid, W. Ying Chow, W. P. W. Lau and M. J. Duer, Biosci. Rep., 2014, 34, e00096.
37. M. Brownlee, Nature, 2001, 414, 813–820.
38. D. Aronson, Adv. Cardiol., 2008, 45, 1–16.
39. S. S. Chung, E. C. Ho, K. S. Lam and S. K. Chung, J. Am. Soc. Nephrol., 2003, 14, S233–S236.
40. S. F. Yan, R. Ramasamy and A. M. Schmidt, Nat. Clin. Pract. Endocrinol. Metab., 2008, 4, 285–293.
41. Y. Hamada, N. Araki, N. Koh, J. Nakamura, S. Horiuchi and N. Hotta, Biochem. Biophys. Res. Commun., 1996, 228, 539–543.
42. C. Henning, K. Liehr, M. Girndt, C. Ulrich and M. A. Glomb, J. Biol. Chem., 2014, 289, 28676–28688.
43. R. Gomes, M. Sousa Silva, A. Quintas, C. Cordeiro, A. Freire, P. Pereira, A. Martins, E. Monteiro, E. Barroso and A. Ponces Freire, Biochem. J., 2005, 385, 339–345.
44. J. Kim, O. S. Kim, C.-S. Kim, E. Sohn, K. Jo and J. S. Kim, Exp. Mol. Med., 2012, 44, 167–175.
45. S. Reddy, J. Bichler, K. J. Wells-Knecht, S. R. Thorpe and J. W. Baynes, Biochemistry, 1995, 34, 10872–10878.
46. K. Ikeda, T. Higashi, H. Sano, Y. Jinnouchi, M. Yoshida, T. Araki, S. Ueda and S. Horiuchi, Biochemistry, 1996, 35, 8075–8083.
47. M. L. M. Lieuw-A-Fa, V. W. M. van Hinsbergh, T. Teerlink, R. Barto, J. Twisk, C. D. A. Stehouwer and C. G. Schalkwijk, Nephrol., Dial., Transplant., 2004, 19, 631–636.
48. S. S. Sivan, E. Tsitron, E. Wachtel, P. Roughley, N. Sakkee, F. van der Ham, J. Degroot and A. Maroudas, Biochem. J., 2006, 399, 29–35.
49. Y. Koyama, Y. Takeishi, T. Arimoto, T. Niizeki, T. Shishido, H. Takahashi, N. Nozaki, O. Hirono, Y. Tsunoda, J. Nitobe, T. Watanabe and I. Kubota, J. Card. Failure, 2007, 13, 199–206.
50. S. F. Yan, R. Ramasamy, Y. Naka and A. M. Schmidt, Circ. Res., 2003, 93, 1159–1169.
51. R. Ramasamy, S. J. Vannucci, S. S. Yan, K. Herold, S. F. Yan and A. M. Schmidt, Glycobiology, 2005, 15, 10.
52. C. Ott, K. Jacobs, E. Haucke, A. Navarrete Santos, T. Grune and A. Simm, Redox Biol., 2014, 2, 411–429.
53. R. Ramasamy, S. F. Yan and A. M. Schmidt, in Atherosclerosis, John Wiley & Sons, Inc, 2015, pp. 27–41.
54. A. W. Stitt, Exp. Mol. Pathol., 2003, 75, 95–108.
55. R. E. Perry, M. S. Swamy and E. C. Abraham, Exp. Eye Res., 1987, 44, 269–282.
56. M. S. Swamy and E. C. Abraham, Invest. Ophthalmol. Visual Sci., 1987, 28, 1693–1701.
57. M. S. Swamy, C. Tsai, A. Abraham and E. C. Abraham, Exp. Eye Res., 1993, 56, 177–185.
58. M. S. Swamy and E. C. Abraham, Invest. Ophthalmol. Visual Sci., 1989, 30, 1120–1126.
59. H.-P. Hammes, A. Alt, T. Niwa, T. J. Clausen, G. R. Bretzel, M. Brownlee and D. E. Schleicher, Diabetologia, 1999, 42, 728–736.
60. B. O. Boehm, S. Schilling, S. Rosinger, G. E. Lang, G. K. Lang, R. Kientsch-Engel and P. Stahl, Diabetologia, 2004, 47, 1376–1379.
61. D. K. Karumanchi, N. Karunaratne, L. Lurio, J. P. Dillon and E. R. Gaillard, Amino Acids, 2015, 47, 2601–2608.
62. K. Sugimoto, M. Yasujima and S. Yagihashi, Curr. Pharm. Des., 2008, 14, 953–961.
63. H. Vlassara, M. Brownlee and A. Cerami, J. Exp. Med., 1984, 160, 197–207.
64. A. M. Vincent, J. W. Russell, P. Low and E. L. Feldman, Endocr. Rev., 2004, 25, 612–628.
65. B. Bouma, L. M. Kroon-Batenburg, Y. P. Wu, B. Brunjes, G. Posthuma, O. Kranenburg, P. G. de Groot, E. E. Voest and M. F. Gebbink, J. Biol. Chem., 2003, 278, 41810–41819.
66. X. H. Li, L. L. Du, X. S. Cheng, X. Jiang, Y. Zhang, B. L. Lv, R. Liu, J. Z. Wang and X. W. Zhou, Cell Death Dis., 2013, 4, e673.
67. N. Sasaki, R. Fukatsu, K. Tsuzuki, Y. Hayashi, T. Yoshida, N. Fujii, T. Koike, I. Wakayama, R. Yanagihara, R. Garruto, N. Amano and Z. Makita, Am. J. Pathol., 1998, 153, 1149–1155.
68. G. Münch, B. Westcott, T. Menini and A. Gugliucci, Amino Acids, 2010, 42, 1221–1236.
69. E. Guerrero, P. Vasudevaraju, M. L. Hegde, G. B. Britton and K. S. Rao, Mol. Neurobiol., 2012, 47, 525–536.
70. V. Jakus and N. Rietbrock, Physiol. Res., 2004, 53, 131–142.
71. S. Yamagishi, K. Nakamura and T. Imaizumi, Curr. Diabetes Rev., 2005, 1, 93–106.
72. C. G. Schalkwijk and T. Miyata, Amino Acids, 2012, 42, 1193–1204.
73. A. Simm, J. Proteomics, 2013, 92, 248–259.
74. Z. Makita, S. Radoff, E. J. Rayfield, Z. Yang, E. Skolnik, V. Delaney, E. A. Friedman, A. Cerami and H. Vlassara, N. Engl. J. Med., 1991, 325, 836–842.
75. M. C. Thomas, J. M. Forbes and M. E. Cooper, Am. J. Therapeut., 2005, 12, 562–572.
76. M. Kalousova, T. Zima, P. Popov, P. Spacek, M. Braun, J. Soukupova, K. Pelinkova and R. Kientsch-Engel, Alcohol Alcohol., 2004, 39, 316–320.
77. T. Miyata, Y. Wada, Z. Cai, Y. Iida, K. Horie, Y. Yasuda, K. Maeda, K. Kurokawa and C. van Ypersele de Strihou, Kidney Int., 1997, 51, 1170–1181.
78. S. K. Mallipattu and J. Uribarri, Curr. Opin. Nephrol. Hypertens., 2014, 23, 547–554.
79. H. Vlassara, Ann. Med., 1996, 28, 419–426.
80. G. Basta, A. M. Schmidt and R. De Caterina, Cardiovasc. Res., 2004, 63, 582–592.
81. P. Gkogkolou and M. Böhm, Derm.-Endocrinol., 2012, 4, 259–270.
82. H. Hideyuki and Y. Sho-ichi, Curr. Pharm. Des., 2008, 14, 969–972.
83. H. Sharaf, S. Matou-Nasri, Q. Wang, Z. Rabhan, H. Al-Eidi, A. Al Abdulrahman and N. Ahmed, Biochim. Biophys. Acta, Mol. Basis Dis., 2015, 1852, 429–441.
84. P. B. Pun and M. P. Murphy, Int. J. Cell Biol., 2012, 843505, 21.
85. P. A. Cloos and S. Christgau, Matrix Biol., 2002, 21, 39–52.
86. P. C. Cloos and S. Christgau, Biogerontology, 2004, 5, 139–158.
87. F. W. Danby, Clin. Dermatol., 2010, 28, 409–411.
88. J. A. Miller, E. Gravallese and H. F. Bunn, J. Clin. Invest., 1980, 65, 896–901.
89. A. C. Boyd, Y. H. A. Abdel-Wahab, A. M. McKillop, H. McNulty, C. R. Barnett, F. P. M. O'Harte and P. R. Flatt, Biochim. Biophys. Acta, Gen. Subj., 2000, 1523, 128–134.
90. S. Sen, M. Kar, A. Roy and A. S. Chakraborti, Biophys. Chem., 2005, 113, 289–298.
91. B. Hiller and P. C. Lorenzen, Food Res. Int., 2010, 43, 1155–1166.
92. A. Lapolla, D. Fedele, R. Reitano, N. C. Aricò, R. Seraglia, P. Traldi, E. Marotta and R. Tonani, J. Am. Soc. Mass Spectrom., 2004, 15, 496–509.
93. M. Wuhrer, A. M. Deelder and C. H. Hokke, J. Chromatogr. B: Anal. Technol. Biomed. Life Sci., 2005, 825, 124–133.
94. A. Lapolla, D. Fedele, R. Seraglia and P. Traldi, Mass Spectrom. Rev., 2006, 25, 775–797.
95. Q. Zhang, J. M. Ames, R. D. Smith, J. W. Baynes and T. O. Metz, J. Proteome Res., 2009, 8, 754–769.
96. O. S. Barnaby, C. Wa, R. L. Cerny, W. Clarke and D. S. Hage, Clin. Chim. Acta, 2010, 411, 1102–1110.
97. D. C. Carter, X. M. He, S. H. Munson, P. D. Twigg, K. M. Gernert, M. B. Broom and T. Y. Miller, Science, 1989, 244, 1195–1198.
98. D. C. Carter and J. X. Ho, Adv. Protein Chem., 1994, 45, 153–203.
99. X. M. He and D. C. Carter, Nature, 1992, 358, 209–215.
100. T. Peters Jr, in All About Albumin, Academic Press, San Diego, 1995, pp. 9–75.
101. A. Bujacz, Acta Crystallogr., Sect. D: Biol. Crystallogr., 2012, 68, 1278–1289.
102. S. Sugio, A. Kashima, S. Mochizuki, M. Noda and K. Kobayashi, Protein Eng., 1999, 12, 439–446.
103. S. Curry, H. Mandelkow, P. Brick and N. Franks, Nat. Struct. Biol., 1998, 5, 827–835.
104. G. Sudlow, D. J. Birkett and D. N. Wade, Mol. Pharmacol., 1975, 11, 824–832.
105. G. Sudlow, D. J. Birkett and D. N. Wade, Mol. Pharmacol., 1976, 12, 1052–1061.
106. J. Ghuman, P. A. Zunszain, I. Petitpas, A. A. Bhattacharya, M. Otagiri and S. Curry, J. Mol. Biol., 2005, 353, 38–52.
107. H. Lin, J. Lan, M. Guan, F. Sheng and H. Zhang, Spectrochim. Acta, Part A, 2009, 73, 936–941.
108. P. N. Naik, S. A. Chimatadar and S. T. Nandibewoor, Spectrochim. Acta, Part A, 2009, 73, 841–845.
109. A. Sułkowska, J. Mol. Struct., 2002, 614, 227–232.
110. M. Fasano, S. Curry, E. Terreno, M. Galliano, G. Fanali, P. Narciso, S. Notari and P. Ascenzi, IUBMB Life, 2005, 57, 787–796.
111. S. Curry, Drug Metab. Pharmacokinet., 2009, 24, 342–357.
112. V. M. Rosenoer, in Albumin: Structure, Function and Uses, Pergamon, 1977, pp. 345–367.
113. J. Figge, T. H. Rossing and V. Fencl, J. Lab. Clin. Med., 1991, 117, 453–467.
114. G. Fanali, A. di Masi, V. Trezza, M. Marino, M. Fasano and P. Ascenzi, Mol. Aspects Med., 2012, 33, 209–290.
115. I. Matei, S. Ionescu and M. Hillebrand, Spectrochim. Acta, Part A, 2012, 96, 709–715.
116. S. Tabassum, W. M. Al-Asbahy, M. Afzal and F. Arjmand, J. Photochem. Photobiol., B, 2012, 114, 132–139.
117. Y. Sameena, N. Sudha, S. Chandrasekaran and I. M. V. Enoch, J. Biol. Phys., 2014, 40, 347–367.
118. P. Caironi, T. Langer and L. Gattinoni, Curr. Opin. Crit. Care, 2015, 21, 302–308.
119. I. Nowak and L. M. Shaw, Clin. Chem., 1995, 41, 1011–1017.
120. Z. M. Wang, J. X. Ho, J. R. Ruble, J. Rose, F. Ruker, M. Ellenburg, R. Murphy, J. Click, E. Soistman, L. Wilkerson and D. C. Carter, Biochim. Biophys. Acta, 2013, 12, 6.
121. K. Yamasaki, V. T. Chuang, T. Maruyama and M. Otagiri, Biochim. Biophys. Acta, 2013, 12, 10.
122. A. A. Bhattacharya, S. Curry and N. P. Franks, J. Biol. Chem., 2000, 275, 38731–38738.
123. I. Petitpas, C. E. Petersen, C. E. Ha, A. A. Bhattacharya, P. A. Zunszain, J. Ghuman, N. V. Bhagavan and S. Curry, Proc. Natl. Acad. Sci. U. S. A., 2003, 100, 6440–6445.
124. P. A. Zunszain, J. Ghuman, T. Komatsu, E. Tsuchida and S. Curry, BMC Struct. Biol., 2003, 3, 7.
125. F. Zsila, Mol. Pharm., 2013, 10, 1668–1682.
126. S. Watanabe, T. Tani and M. Seno, Biochim. Biophys. Acta, 1991, 4, 275–284.
127. G. L. Tritsch, C. E. Rathke, N. E. Tritsch and C. M. Weiss, J. Biol. Chem., 1961, 236, 3163–3167.
128. I. Petitpas, A. A. Bhattacharya, S. Twine, M. East and S. Curry, J. Biol. Chem., 2001, 276, 22804–22809.
129. W. Bal, M. Sokołowska, E. Kurowska and P. Faller, Biochim. Biophys. Acta, Gen. Subj., 2013, 1830, 5444–5455.
130. H. A. Saroff and M. S. Lewis, J. Phys. Chem., 1963, 67, 1211–1216.
131. C. B. Berde, B. S. Hudson, R. D. Simoni and L. A. Sklar, J. Biol. Chem., 1979, 254, 391–400.
132. B. Sengupta and P. K. Sengupta, Biochem. Biophys. Res. Commun., 2002, 299, 400–403.
133. J. Kang, Y. Liu, M.-X. Xie, S. Li, M. Jiang and Y.-D. Wang, Biochim. Biophys. Acta, Gen. Subj., 2004, 1674, 205–214.
134. J. Min, X. Meng-Xia, Z. Dong, L. Yuan, L. Xiao-Yu and C. Xing, J. Mol. Struct., 2004, 692, 71–80.
135. M.-X. Xie, X.-Y. Xu and Y.-D. Wang, Biochim. Biophys. Acta, Gen. Subj., 2005, 1724, 215–224.
136. H.-X. Zhang, X. Huang, P. Mei, K.-H. Li and C.-N. Yan, J. Fluoresc., 2006, 16, 287–294.
137. Y.-Q. Wang, H.-M. Zhang, G.-C. Zhang, W.-H. Tao, Z.-H. Fei and Z.-T. Liu, J. Pharm. Biomed. Anal., 2007, 43, 1869–1875.
138. J. Xiao, J. Shi, H. Cao, S. Wu, F. Ren and M. Xu, J. Pharm. Biomed. Anal., 2007, 45, 609–615.
139. S. N. Khan, B. Islam, R. Yennamalli, A. Sultan, N. Subbarao and A. U. Khan, Eur. J. Pharm. Sci., 2008, 35, 371–382.
140. N. Wang, L. Ye, F. Yan and R. Xu, Int. J. Pharm., 2008, 351, 55–60.
141. Y.-J. Hu, H.-L. Yue, X.-L. Li, S.-S. Zhang, E. Tang and L.-P. Zhang, J. Photochem. Photobiol., B, 2012, 112, 16–22.
142. S. Awasthi and N. T. Saraswathi, J. Biomol. Struct. Dyn., 2015, 1–9.
143. V. Sinisi, C. Forzato, N. Cefarin, L. Navarini and F. Berti, Food Chem., 2015, 168, 332–340.
144. S. Tayyab, M. S. Zaroog, S. R. Feroz, S. B. Mohamad and S. N. A. Malek, Int. J. Pharm., 2015, 491, 352–358.
145. Y. Kurono, I. Kushida, H. Tanaka and K. Ikeda, Chem. Pharm. Bull., 1992, 40, 2169–2172.
146. N. Dubois-Presle, F. Lapicque, M. H. Maurice, S. Fournel-Gigleux, J. Magdalou, M. Abiteboul, G. Siest and P. Netter, Mol. Pharmacol., 1995, 47, 647–653.
147. A. Salvi, P. A. Carrupt, J. M. Mayer and B. Testa, Drug Metab. Dispos., 1997, 25, 395–398.
148. Y. Sakurai, S.-F. Ma, H. Watanabe, N. Yamaotsu, S. Hirono, Y. Kurono, U. Kragh-Hansen and M. Otagiri, Pharm. Res., 2004, 21, 285–292.
149. N. Ahmed, D. Dobler, M. Dean and P. J. Thornalley, J. Biol. Chem., 2005, 280, 5724–5732.
150. F. Yang, C. Bian, L. Zhu, G. Zhao, Z. Huang and M. Huang, J. Struct. Biol., 2007, 157, 348–355.
151. Y. Wang, S. Wang and M. Huang, Curr. Pharm. Des., 2015, 21, 1831–1836.
152. J. Córdova, J. D. Ryan, B. B. Boonyaratanakornkit and D. S. Clark, Enzyme Microb. Technol., 2008, 42, 278–283.
153. H. Watanabe, S. Tanase, K. Nakajou, T. Maruyama, U. Kragh-Hansen and M. Otagiri, Biochem. J., 2000, 3, 813–819.
154. N. G. Watkins, S. R. Thorpe and J. W. Baynes, J. Biol. Chem., 1985, 260, 10629–10636.
155. R. L. Garlick and J. S. Mazer, J. Biol. Chem., 1983, 258, 6142–6146.
156. N. Iberg and R. Fluckiger, J. Biol. Chem., 1986, 261, 13542–13545.
157. C. Wa, R. L. Cerny, W. A. Clarke and D. S. Hage, Clin. Chim. Acta, 2007, 385, 48–60.
158. A. Frolov and R. Hoffmann, Anal. Bioanal. Chem., 2010, 397, 2349–2356.
159. O. S. Barnaby, R. L. Cerny, W. Clarke and D. S. Hage, Clin. Chim. Acta, 2011, 412, 277–285.
160. J. Anguizola, R. Matsuda, O. S. Barnaby, K. S. Hoy, C. Wa, E. DeBolt, M. Koke and D. S. Hage, Clin. Chim. Acta, 2013, 425, 64–76.
161. C. E. Guthrow, M. A. Morris, J. F. Day, S. R. Thorpe and J. W. Baynes, Proc. Natl. Acad. Sci. U. S. A., 1979, 76, 4258–4261.
162. K. F. McFarland, E. W. Catalano, J. F. Day, S. R. Thorpe and J. W. Baynes, Diabetes, 1979, 28, 1011–1014.
163. P. Rondeau and E. Bourdon, Biochimie, 2011, 93, 645–658.
164. S. Awasthi, N. A. Murugan and N. T. Saraswathi, Mol. Pharm., 2015, 12, 3312–3322.
165. J. Baraka-Vidot, C. Planesse, O. Meilhac, V. Militello, J. van den Elsen, E. Bourdon and P. Rondeau, Biochemistry, 2015, 54, 3051–3062.
166. F. Yang, C. Bian, L. Zhu, G. Zhao, Z. Huang and M. Huang, J. Struct. Biol., 2007, 157, 348–355.
167. D. Buttar, N. Colclough, S. Gerhardt, P. A. MacFaul, S. D. Phillips, A. Plowright, P. Whittamore, K. Tam, K. Maskos, S. Steinbacher and H. Steuber, Bioorg. Med. Chem., 2010, 18, 7486–7496.
168. A. J. Ryan, J. Ghuman, P. A. Zunszain, C. W. Chung and S. Curry, J. Struct. Biol., 2011, 174, 84–91.
169. N. Shaklai, R. L. Garlick and H. F. Bunn, J. Biol. Chem., 1984, 259, 3812–3817.
170. P. J. Coussons, J. Jacoby, A. McKay, S. M. Kelly, N. C. Price and J. V. Hunt, Free Radical Biol. Med., 1997, 22, 1217–1227.
171. K. Nakajou, H. Watanabe, U. Kragh-Hansen, T. Maruyama and M. Otagiri, Biochim. Biophys. Acta, 2003, 13, 2–3.
172. R. Kisugi, T. Kouzuma, T. Yamamoto, S. Akizuki, H. Miyamoto, Y. Someya, J. Yokoyama, I. Abe, N. Hirai and A. Ohnishi, Clin. Chim. Acta, 2007, 382, 59–64.
173. N. Sattarahmady, A. A. Moosavi-Movahedi, F. Ahmad, G. H. Hakimelahi, M. Habibi-Rezaei, A. A. Saboury and N. Sheibani, Biochim. Biophys. Acta, 2007, 6, 933–942.
174. R. Khodarahmi, S. A. Karimi, M. R. Ashrafi Kooshk, S. A. Ghadami, S. Ghobadi and M. Amani, Spectrochim. Acta, Part A, 2012, 89, 177–186.
175. H. Cao, T. Chen and Y. Shi, Curr. Med. Chem., 2015, 22, 4–13.
176. V. E. Syakhovich, N. T. Saraswathi, M. Ruff, S. B. Bokut and D. Moras, Acta Crystallogr., Sect. F: Struct. Biol. Cryst. Commun., 2006, 62, 106–109.
177. M. W. Khan, Z. Rasheed, W. A. Khan and R. Ali, Biochemistry, 2007, 72, 146–152.
178. A. Mohamadi-Nejad, A. A. Moosavi-Movahedi, S. Safarian, M. H. Naderi-Manesh, B. Ranjbar, B. Farzami, H. Mostafavi, M. B. Larijani and G. H. Hakimelahi, Thermochim. Acta, 2002, 389, 141–151.
179. M. E. Obrenovich and V. M. Monnier, Sci. Aging Knowl. Environ., 2004, 2, pe3.
180. R. GhoshMoulick, J. Bhattacharya, S. Roy, S. Basak and A. K. Dasgupta, Biochim. Biophys. Acta, 2007, 2, 233–242.
181. S. W. Vetter and V. S. Indurthi, Clin. Chim. Acta, 2011, 412, 2105–2116.
182. D. L. Mendez, R. A. Jensen, L. A. McElroy, J. M. Pena and R. M. Esquerra, Arch. Biochem. Biophys., 2005, 444, 92–99.
183. P. Rondeau, G. Navarra, F. Cacciabaudo, M. Leone, E. Bourdon and V. Militello, Biochim. Biophys. Acta, 2010, 4, 789–798.
184. A. Guerin-Dubourg, A. Catan, E. Bourdon and P. Rondeau, Diabetes Metab., 2012, 38, 171–178.
185. S. Chesne, P. Rondeau, S. Armenta and E. Bourdon, Biochimie, 2006, 88, 1467–1477.
186. M. Shahani, F. Daneshi-Mehr, R. Tadayon, B. Hoseinzade Salavati, A. R. Akbar Zadeh-Baghban, A. Zamanian and M. Rezaei-Tavirani, Iran. J. Pharm. Res., 2013, 12, 185–191.
187. X. Bai, Z. Wang, C. Huang and L. Chi, Molecules, 2012, 17, 8782–8794.
188. P. Rondeau, S. Armenta, H. Caillens, S. Chesne and E. Bourdon, Arch. Biochem. Biophys., 2007, 460, 141–150.
189. Y. Wei, L. Chen, J. Chen, L. Ge and R. Q. He, BMC Cell Biol., 2009, 10, 1471–2121.
190. S. Allarakha, P. Ahmad, M. Ishtikhar, M. S. Zaheer, S. S. Siddiqi, Moinuddin and A. Ali, IUBMB Life, 2015, 67, 338–347.
191. N. Sattarahmady, A. A. Moosavi-Movahedi, M. Habibi-Rezaei, S. Ahmadian, A. A. Saboury, H. Heli and N. Sheibani, Carbohydr. Res., 2008, 343, 2229–2234.
192. C. Iannuzzi, G. Irace and I. Sirangelo, Front. Mol. Biosci., 2014, 1, 9.
193. C. Dufour and O. Dangles, Biochim. Biophys. Acta, 2005, 18, 1–3.
194. H. G. Mahesha, S. A. Singh, N. Srinivasan and A. G. Rao, FEBS J., 2006, 273, 451–467.
195. A. Bolli, M. Marino, G. Rimbach, G. Fanali, M. Fasano and P. Ascenzi, Biochem. Biophys. Res. Commun., 2010, 398, 444–449.
196. M. Pesavento and A. Profumo, Talanta, 1991, 38, 1099–1106.
197. S. M. T. Shaikh, J. Seetharamappa, P. B. Kandagal, D. H. Manjunatha and S. Ashoka, Dyes Pigm., 2007, 74, 665–671.
198. N. Barbero, E. Barni, C. Barolo, P. Quagliotto, G. Viscardi, L. Napione, S. Pavan and F. Bussolino, Dyes Pigm., 2009, 80, 307–313.
199. D. V. Suresh, H. G. Mahesha, A. G. Rao and K. Srinivasan, Biopolymers, 2007, 86, 265–275.
200. Y. Q. Wang, H. M. Zhang, J. Cao and B. P. Tang, J. Photochem. Photobiol., B, 2014, 138, 182–190.
201. K. Koizumi, C. Ikeda, M. Ito, J. Suzuki, T. Kinoshita, K. Yasukawa and T. Hanai, Biomed. Chromatogr., 1998, 12, 203–210.
202. J. Baraka-Vidot, A. Guerin-Dubourg, E. Bourdon and P. Rondeau, Biochimie, 2012, 94, 1960–1967.
203. M. P. Cohen, Biochim. Biophys. Acta, 2013, 12, 23.
204. Y. Wang, H. Yu, X. Shi, Z. Luo, D. Lin and M. Huang, J. Biol. Chem., 2013, 288, 15980–15987.
205. T. Enokiya, Y. Muraki, T. Iwamoto and M. Okuda, Int. J. Antimicrob. Agents, 2015, 46, 164–168.
206. J. Sabah, E. McConkey, R. Welti, K. Albin and L. J. Takemoto, Exp. Eye Res., 2005, 80, 31–36.
207. G. J. van der Vusse, Drug Metab. Pharmacokinet., 2009, 24, 300–307.
208. D. Blache, E. Bourdon, P. Salloignon, G. Lucchi, P. Ducoroy, J. M. Petit, B. Verges and L. Lagrost, Diabetes, 2015, 64, 960–972.
209. B. G. Stegmayr, New insight in impaired binding capacity for albumin in uraemic patients, Acta Physiol., 2015, 215(1), 5–8.
210. E. Yamazaki, M. Inagaki, O. Kurita and T. Inoue, J. Biosci., 2005, 30, 475–481.
211. E. Bourdon, N. Loreau and D. Blache, FASEB J., 1999, 13, 233–244.
212. P. Faure, N. Wiernsperger, C. Polge, A. Favier and S. Halimi, Clin. Sci., 2008, 114, 251–256.
213. S. Y. Yang, Y. J. Chen, P. H. Kao and L. S. Chang, Arch. Biochem. Biophys., 2014, 564, 43–51.
214. C. M. Zheng, W. Y. Ma, C. C. Wu and K. C. Lu, Clin. Chim. Acta, 2012, 413, 1555–1561.
215. A. Singha Roy, P. Ghosh and S. Dasgupta, J. Biomol. Struct. Dyn., 2015, 30, 1–8.
216. W. Xu, L. Chen and R. Shao, Curr. Drug Metab., 2014, 15, 116–119.
217. F. N. Ziyadeh and M. P. Cohen, Mol. Cell. Biochem., 1993, 125, 19–25.
218. M. P. Cohen and F. N. Ziyadeh, Kidney Int., 1994, 45, 475–484.
219. S. Awasthi, S. K. Gayathiri, R. Ramya, R. Duraichelvan, A. Dhason and N. T. Saraswathi, Appl. Biochem. Biotechnol., 2015, 177, 1013–1024.
220. Y. Hattori, H. Kakishita, K. Akimoto, M. Matsumura and K. Kasai, Biochem. Biophys. Res. Commun., 2001, 281, 891–896.
221. Y. Hattori, M. Suzuki, S. Hattori and K. Kasai, Hypertension, 2002, 39, 22–28.
222. A. Amore, P. Cirina, S. Mitola, L. Peruzzi, B. Gianoglio, I. Rabbone, C. Sacchetti, F. Cerutti, C. Grillo and R. Coppo, Kidney Int., 1997, 51, 27–35.
223. A. M. Schmidt, C. Esposito, J. Brett, S. Ogawa, M. Clauss, M. Kirstein, S. Radoff, H. Vlassara and D. Stern, in Mononuclear Phagocytes, ed. R. van Furth, Springer, Netherlands, 1992, ch. 27, pp. 202–207.
224. N. A. Ansari, Moinuddin, K. Alam and A. Ali, Hum. Immunol., 2009, 70, 417–424.
225. N. A. Ansari and D. Dash, Aging and Disease, 2013, 4, 50–56.
226. N. A. Ansari, Moinuddin, A. R. Mir, S. Habib, K. Alam, A. Ali and R. H. Khan, Cell Biochem. Biophys., 2014, 70, 857–865.

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