Lysine residue 199 of human serum albumin is modified by acetylsalicylic acid

Walker, John E.

doi:10.1016/0014-5793(76)80496-6

Cited by 117 publications

(50 citation statements)

References 11 publications

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“…Lys195 was found to interact with acyl glucuronides of tolmetin and benoxaprofen, likely via Schiff base condensation when the acyl glucuronides of tolmetin and benoxaprofen were incubated with human plasma (Qiu et al, 1998). Alkylation of Lys199 with acetylsalicylic acid via acid-based neutralization was reported (Walker, 1976) as well.…”

Section: Discussionmentioning

confidence: 95%

Characterization of HKI-272 Covalent Binding to Human Serum Albumin

Wang¹,

Li-Chan²,

Atherton³

et al. 2010

Drug Metab Dispos

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Section: Discussionmentioning

confidence: 95%

Characterization of HKI-272 Covalent Binding to Human Serum Albumin

Wang¹,

Li-Chan²,

Atherton³

et al. 2010

Drug Metab Dispos

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“…Thus, it is likely that components of human serum other than albumin may also catalyze the isoxazole ring opening in leflunomide. Overall, the involvement of albumin in leflunomide metabolism is not surprising considering its well established role in the metabolism of xenobiotics, particularly its esterase activity with drugs such as aspirin (Walker, 1976) and its ability to catalyze ␤-elimination reactions on drugs such as 4-hydroxycyclophosphamide (Kwon et al, 1987), felbamate (Roller et al, 2002), and certain prostaglandin analogs (Fitzpatrick et al, 1984;Kozak et al, 2001).…”

Section: Discussionmentioning

confidence: 99%

In VITRO METABOLISM STUDIES ON THE ISOXAZOLE RING SCISSION IN THE ANTI-INFLAMMATORY AGENT LEFLUNOMIDE TO ITS ACTIVE Α-Cyanoenol METABOLITE A771726: MECHANISTIC SIMILARITIES WITH THE CYTOCHROME P450-Catalyzed DEHYDRATION OF ALDOXIMES

Kalgutkar

Nguyen²,

Vaz³

et al. 2003

Drug Metab Dispos

108

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This article is available online at http://dmd.aspetjournals.org ABSTRACT:The 3-unsubstituted isoxazole ring in the anti-inflammatory drug leflunomide undergoes a unique N-O bond cleavage to the active ␣-cyanoenol metabolite A771726, which resides in the same oxidation state as the parent. In vitro studies were conducted to characterize drug-metabolizing enzyme(s) responsible for ring opening and to gain insight into the mechanism of ring opening. Under physiological conditions, leflunomide was converted to A771726 in rat and human plasma (rat plasma, t 1/2 ‫؍‬ 36 min; human plasma, t 1/2 ‫؍‬ 12 min) and whole blood (rat blood, t 1/2 ‫؍‬ 59 min; human blood, t 1/2 ‫؍‬ 43 min). Human serum albumin also catalyzed A771726 formation, albeit at a much slower rate (t 1/2 ‫؍‬ 110 min). Rat and human liver microsomes also demonstrated NADPH-dependent A771726 formation (human liver microsomes, V max ‫؍‬ 1,797 pmol/min/mg and K m ‫؍‬ 274 M). Leflunomide metabolism in microsomes was sensitive to furafylline treatment, suggesting P4501A2 involvement. 3-Methylleflunomide, which contained a 3-methyl substituent on the isoxazole ring, was resistant to ring opening in base, plasma, blood, and liver microsomes. In microsomes, two monohydroxylated metabolites were formed, and metabolite identification studies established the 3-and the 5-methyl groups on the isoxazole ring as sites of hydroxylation. These results indicate that the C3-H in leflunomide is essential for ring opening. Although A771726 formation in human liver microsomes or recombinant P4501A2 required NADPH, its formation was greatly reduced by oxygen or carbon monoxide, suggesting that the isoxazole ring opening was catalyzed by the P450Fe(II) form of the enzyme. A mechanism for the P450-mediated ring scission is proposed in which the isoxazole ring nitrogen or oxygen coordinates to the reduced form of the heme followed by charge transfer from P450Fe(II) to the C‫؍‬N bond or deprotonation of the C3-H, which results in a cleavage of the N-O bond.

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“…21 Another pharmacologic acetylating agent, aspirin (acetyl salicylic; ASA), which is a common anti-inflammatory agent, acetylated Lys residues in several molecules including antithrombin III, 22 hemoglobin, 23,24 fibrinogen 25 and BSA. 26 Since ASA can be administered orally to humans, it could serve as a practical method to modulate the activity of TGM2.…”

Section: Resultsmentioning

confidence: 99%

Human tissue transglutaminase is inhibited by pharmacologic and chemical acetylation

2010

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Human tissue transglutaminase (TGM2) is implicated in the pathogenesis of several neurodegenerative disorders including Alzheimer's, Parkinson's and expanded polyglutamine (polyQ) diseases. TGM2 promotes formation of soluble and insoluble high molecular weight aggregates by catalyzing a covalent linkage between peptide-bound Q residues in polyQ proteins and a peptide-bound Lys residue. Therapeutic approaches to modulate the activity of TGM2 are needed to proceed with studies to test the efficacy of TGM2 inhibition in disease processes. We investigated whether acetylation of Lys-residues by sulfosuccinimidyl acetate (SNA) or aspirin (ASA) would alter the crosslinking activity of TGM2. Acetylation by either SNA and/or ASA resulted in a loss of >90% of crosslinking activity. The Lys residues that were critical for inhibition were identified by mass spectrometry as Lys . Hence, acetylation of Lys-residues may modulate the enzymatic function of TGM2 in vivo and offer a novel approach to treatment of TGM2 mediated disorders.

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Lysine residue 199 of human serum albumin is modified by acetylsalicylic acid

Cited by 117 publications

References 11 publications

Characterization of HKI-272 Covalent Binding to Human Serum Albumin

Characterization of HKI-272 Covalent Binding to Human Serum Albumin

In VITRO METABOLISM STUDIES ON THE ISOXAZOLE RING SCISSION IN THE ANTI-INFLAMMATORY AGENT LEFLUNOMIDE TO ITS ACTIVE Α-Cyanoenol METABOLITE A771726: MECHANISTIC SIMILARITIES WITH THE CYTOCHROME P450-Catalyzed DEHYDRATION OF ALDOXIMES

Human tissue transglutaminase is inhibited by pharmacologic and chemical acetylation

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