Cystathionine gamma-synthase (CGS)

Cystathionine gamma-synthase (CGS) is a pyridoxal 5-phosphate (PLP)-dependent enzyme that catalyzes the first committed step in the biosynthesis of methionine in plants and microorganisms (EC 2.5.1.48). It facilitates the conversion of O-succinyl-L-homoserine (in bacteria) or O-phospho-L-homoserine (in plants) and L-cysteine into L-cystathionine (Wikipedia, 2024). Because this enzyme is essential for the survival of these organisms and is notably absent in mammals, it represents a highly attractive target for the development of novel antimicrobial agents and herbicides (PMID: 33773037). Inhibition of CGS leads to methionine depletion, which disrupts protein synthesis and halts growth in pathogens such as Mycobacterium tuberculosis and various weed species. Various small molecules, including the natural product rhizobitoxine and synthetic phenyl-benzamide derivatives, have been identified as potent inhibitors that bind to the enzyme's active site or its PLP cofactor (PMID: 11514512). Therapeutic strategies targeting CGS aim to exploit the metabolic differences between pathogens/weeds and their hosts to ensure high selectivity and minimal human toxicity.

Other names

O-succinylhomoserine (thiol)-lyaseO-succinyl-L-homoserine succinate-lyase (adding cysteine)Homoserine O-transsuccinylaseO-succinylhomoserine synthaseO-succinylhomoserine synthetaseCystathionine synthaseCystathionine synthetaseHomoserine transsuccinylase4-O-succinyl-L-homoserine:L-cysteine S-(3-amino-3-carboxypropyl)transferase

Inhibition of the enzyme's catalytic activity, typically through competitive or irreversible binding to the active site or the pyridoxal 5-phosphate (PLP) cofactor, leading to the depletion of methionine and subsequent growth arrest (PMID: 33773037).