Mechanism-based inactivation of pig heart L-alanine transaminase by L-propargylglycine. Half-site reactivity.

Burnett, George H.; Marcotte, Patrick A.; Walsh, Christopher T.

doi:10.1016/s0021-9258(19)85725-3

Cited by 44 publications

(5 citation statements)

References 22 publications

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“…1979), aminotranferases (Marcotte and Walsh 1975; Tanase and Morino 1976; Alston et al. 1980; Burnett et al. 1980) and d ‐amino acid oxidase (EC 1.4.3.3) (Horiike et al.…”

Section: Metabolismmentioning

confidence: 99%

Hydrogen sulfide as a gasotransmitter

Gadalla

Snyder

2010

Journal of Neurochemistry

444

302

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Nitric oxide (NO) and carbon monoxide (CO) are well established as messenger molecules throughout the body, gasotransmitters, based on striking alterations in mice lacking the appropriate biosynthetic enzymes. Hydrogen sulfide (H 2 S) is even more chemically reactive, but until recently there was little definitive evidence for its physiologic formation. Cystathionine b-synthase (EC 4.2.1.22), and cystathionine c-lyase (CSE; EC 4.4.1.1), also known as cystathionine, can generate H 2 S from cyst(e)ine. Very recent studies with mice lacking these enzymes have established that CSE is responsible for H 2 S formation in the periphery, while in the brain cystathionine b-synthase is the biosynthetic enzyme. Endothelial-derived relaxing factor activity is reduced 80% in the mesenteric artery of mice with deletion of CSE, establishing H 2 S as a major physiologic endothelial-derived relaxing factor. H 2 S appears to signal predominantly by S-sulfhydrating cysteines in its target proteins, analogous to S-nitrosylation by NO. Whereas S-nitrosylation typically inhibits enzymes, S-sulfhydration activates them. S-nitrosylation basally affects 1-2% of its target proteins, while 10-25% of H 2 S target proteins are S-sulfhydrated. In summary, H 2 S appears to be a physiologic gasotransmitter of comparable importance to NO and carbon monoxide.

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“…1979), aminotranferases (Marcotte and Walsh 1975; Tanase and Morino 1976; Alston et al. 1980; Burnett et al. 1980) and d ‐amino acid oxidase (EC 1.4.3.3) (Horiike et al.…”

Section: Metabolismmentioning

confidence: 99%

Hydrogen sulfide as a gasotransmitter

Gadalla

Snyder

2010

Journal of Neurochemistry

444

302

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“…With pigeon liver malic enzyme, Hsu & Pry (1980) found that only half the subunits participate in catalysis at any time. Inactivation of the pig heart L-alanine transaminase by Burnett et al (1980) with the mechanism-based inhibitor L-propargylglycine was accomplished by incorporation of only 1 mol of inhibitor per dimer at 97% inhibition of activity. Interestingly, with E. coli glutamine synthetase, such inhibition by ß and ATP causes both diminished catalytic efficiency and ligand binding.…”

Section: L-glumentioning

confidence: 99%

Catalytic cooperativity and subunit interactions in E. coli glutamine synthetase binding and kinetics with methionine sulfoximine and related inhibitors

Wedler¹,

Sugiyama²,

Fisher³

1982

Biochemistry

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“…MGL also produces H 2 S from homocysteine as a substrate, and this activity of MGL can be measured by fluorescence detection with HSip-1. ALT produces pyruvate and L-glutamate from α-ketoglutarate and L-alanine, and is also inhibited by PAG 12 . The enzymatic activity of ALT can be assessed by means of a coupled assay using the reduction of pyruvate to L-lactate with lactate dehydrogenase and NADH and measuring the change in absorption of NADH.…”

Section: Resultsmentioning

confidence: 99%

Discovery of a cystathionine γ-lyase (CSE) selective inhibitor targeting active-site pyridoxal 5′-phosphate (PLP) via Schiff base formation

Echizen,

Hanaoka,

Shimamoto

et al. 2023

Sci Rep

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D,L-Propargylglycine (PAG) has been widely used as a selective inhibitor to investigate the biological functions of cystathionine γ-lyase (CSE), which catalyzes the formation of reactive sulfur species (RSS). However, PAG also inhibits other PLP (pyridoxal-5′-phosphate)-dependent enzymes such as methionine γ-lyase (MGL) and L-alanine transaminase (ALT), so highly selective CSE inhibitors are still required. Here, we performed high-throughput screening (HTS) of a large chemical library and identified oxamic hydrazide 1 as a potent inhibitor of CSE (IC50 = 13 ± 1 μM (mean ± S.E.)) with high selectivity over other PLP-dependent enzymes and RSS-generating enzymes. Inhibitor 1 inhibited the enzymatic activity of human CSE in living cells, indicating that it is sufficiently membrane-permeable. X-Ray crystal structure analysis of the complex of rat CSE (rCSE) with 1 revealed that 1 forms a Schiff base linkage with the cofactor PLP in the active site of rCSE. PLP in the active site may be a promising target for development of selective inhibitors of PLP-dependent enzymes, including RSS-generating enzymes such as cystathionine β-synthase (CBS) and cysteinyl-tRNA synthetase 2 (CARS2), which have unique substrate binding pocket structures.

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Mechanism-based inactivation of pig heart L-alanine transaminase by L-propargylglycine. Half-site reactivity.

Cited by 44 publications

References 22 publications

Hydrogen sulfide as a gasotransmitter

Hydrogen sulfide as a gasotransmitter

Catalytic cooperativity and subunit interactions in E. coli glutamine synthetase binding and kinetics with methionine sulfoximine and related inhibitors

Discovery of a cystathionine γ-lyase (CSE) selective inhibitor targeting active-site pyridoxal 5′-phosphate (PLP) via Schiff base formation

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