Binding of fatty acids facilitates oxidation of cysteine-34 and converts copper–albumin complexes from antioxidants to prooxidants

Gryzunov, Yu. A.; Arroyo, Antonio; Vigne, Jean-Louis; Zhao, Qing; Tyurin, Vladimir A.; Hubel, Carl A.; Gandley, Robin E.; Vladimirov, Yu. A.; Taylor, Robert N.; Kagan, Valerian E.

doi:10.1016/s0003-9861(03)00091-2

Cited by 93 publications

(75 citation statements)

References 54 publications

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“…First, relative amounts of unbound NEFAs may increase, thus raising their potential adverse effects through interactions with lipoproteins and cells. Second, NEFA binding and albumin oxidation of the thiol group are known to be intimately linked, and the more NEFAs bound to albumin, the more Cys 34 was oxidized (49). In comparison with albumin from control subjects, that from T2D patients displayed reduced levels of free thiols and Lys-NH 2 and decreased antioxidant activity (14,42).…”

Section: Discussionmentioning

confidence: 99%

Glycated Albumin With Loss of Fatty Acid Binding Capacity Contributes to Enhanced Arachidonate Oxygenation and Platelet Hyperactivity: Relevance in Patients With Type 2 Diabetes

et al. 2014

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High plasma concentrations of nonesterified fatty acids (NEFAs), transported bound to serum albumin, are associated with type 2 diabetes (T2D). The effects of albumin on platelet function were investigated in vitro. Modifications of albumin, such as those due to glycoxidation, were found in patients with T2D, and the consequences of these modifications on biological mechanisms related to NEFA handling were investigated. Mass spectrometry profiles of albumin from patients with T2D differed from those from healthy control subjects. Diabetic albumin showed impaired NEFA binding capacity, and both structural and functional alterations could be reproduced in vitro by incubating native albumin with glucose and methylglyoxal. Platelets incubated with albumin isolated from patients with T2D aggregated approximately twice as much as platelets incubated with albumin isolated from healthy control subjects. Accordingly, platelets incubated with modified albumin produced significantly higher amounts of arachidonate metabolites than did platelets incubated with control albumin. We concluded that higher amounts of free arachidonate are made available for the generation of active metabolites in platelets when the NEFA binding capacity of albumin is blunted by glycoxidation. This newly described mechanism, in addition to hypoalbuminemia, may contribute to platelet hyperactivity and increased thrombosis, known to occur in patients with T2D.

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Section: Discussionmentioning

confidence: 99%

Glycated Albumin With Loss of Fatty Acid Binding Capacity Contributes to Enhanced Arachidonate Oxygenation and Platelet Hyperactivity: Relevance in Patients With Type 2 Diabetes

et al. 2014

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“…Defatted albumin and N-ethylmaleimide (NEM)-albumin were prepared by treating albumin with charcoal and NEM, respectively, as described previously. 23 a-1 Acid glycoprotein (AGP) and transferrin (Tf) were purchased from Sigma-Aldrich (St. Louis, MO, USA). All chemicals used in the studies were analytical grade.…”

Section: Materials and Methods Materialsmentioning

confidence: 99%

“…The inhibitory effect of defatted albumin (non-FA-Alb) was consistently weaker than that of native albumin (Figure 3a). Moreover, NEM-albumin, with a weaker antioxidant effect, 23 had less of an inhibitory effect than did albumin alone (Figure 3b). …”

Section: Antioxidant Effect Of Albumin On Ttr Amyloid Formationmentioning

confidence: 98%

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Loss of functional albumin triggers acceleration of transthyretin amyloid fibril formation in familial amyloidotic polyneuropathy

Kugimiya

Jono

Saito

et al. 2011

Laboratory Investigation

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Transthyretin (TTR)-related familial amyloidotic polyneuropathy (FAP) is characterized by systemic accumulation of amyloid fibrils caused by a point mutation in the TTR gene. Despite the urgent need for alternative therapeutic strategies, the pathogenesis of FAP still remains elusive. In our study reported here, we focused on albumin, the most abundant protein in plasma, and described the role of albumin in the TTR amyloid-formation process. Patients with FAP evidenced significantly decreased serum albumin levels as the disease progressed. Biacore analysis showed that albumin had a binding affinity for TTR and exhibited higher affinity for TTR amyloid than native TTR. Albumin functioning as an antioxidant effectively suppressed TTR amyloid formation. In patients with FAP, albumin was significantly oxidized as the disease progressed. Moreover, loss of functional albumin accelerated TTR deposition in analbuminemic rats possessing a human variant TTR gene. Taken together, these results indicate that albumin may have an inhibitory role in the TTR amyloid-formation process.

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“…This sensitivity of the thiol to protein conformation is also revealed by the fact that its reactivity is affected by the presence of ligands. For example, fatty acids, which bind to sites relatively distant from Cys34, induce conformational changes at the thiol site and increase the reactivity of the thiol towards disulfides (18,19).…”

Section: Reactivity Of the Albumin Thiolmentioning

confidence: 99%

Oxidation of the albumin thiol to sulfenic acid and its implications in the intravascular compartment

Turell

Carballal

Botti

et al. 2009

Braz J Med Biol Res

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Human serum albumin (HSA) is the most abundant protein in the intravascular compartment. It possesses a single thiol, Cys34, which constitutes ~8 0% of the total thiols in plasma. This thiol is able to scavenge plasma oxidants. A central intermediate in this potential antioxidant activity of human serum albumin is sulfenic acid (HSA-SOH). Work from our laboratories has demonstrated the formation of a relatively stable sulfenic acid in albumin through complementary spectrophotometric and mass spectrometric approaches. Recently, we have been able to obtain quantitative data that allowed us to measure the rate constants of sulfenic acid reactions with molecules of analytical and biological interest. Kinetic considerations led us to conclude that the most likely fate for sulfenic acid formed in the plasma environment is the reaction with low molecular weight thiols to form mixed disulfides, a reversible modification that is actually observed in ~2 5% of circulating albumin. Another possible fate for sulfenic acid is further oxidation to sulfinic and sulfonic acids. These irreversible modifications are also detected in the circulation. Oxidized forms of albumin are increased in different pathophysiological conditions and sulfenic acid lies in a mechanistic junction, relating oxidizing species to final thiol oxidation products.

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Binding of fatty acids facilitates oxidation of cysteine-34 and converts copper–albumin complexes from antioxidants to prooxidants

Cited by 93 publications

References 54 publications

Glycated Albumin With Loss of Fatty Acid Binding Capacity Contributes to Enhanced Arachidonate Oxygenation and Platelet Hyperactivity: Relevance in Patients With Type 2 Diabetes

Glycated Albumin With Loss of Fatty Acid Binding Capacity Contributes to Enhanced Arachidonate Oxygenation and Platelet Hyperactivity: Relevance in Patients With Type 2 Diabetes

Loss of functional albumin triggers acceleration of transthyretin amyloid fibril formation in familial amyloidotic polyneuropathy

Oxidation of the albumin thiol to sulfenic acid and its implications in the intravascular compartment

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