Glycine decarboxylase is an unusual amino acid decarboxylase involved in tumorigenesis.
Glycine decarboxylase (GLDC) is a metabolic oncogene that links glycine metabolism with tumorigenesis. In humans, GLDC is part of a multienzyme complex (which includes the lipoyl-containing H-protein) that couples the decarboxylation of glycine to the biosynthesis of serine. Details of the GLDC-catalyzed glycine decarboxylation reaction are critical to drug development but remain elusive. This is the first report on the mechanism of the GLDC-catalyzed reaction and shows that GLDC is an unusual PLP-containing α-amino acid decarboxylase that removes carbon dioxide from the glycine substrate without releasing the expected amine (methylamine, a metabolic precursor of toxic formaldehyde) as a product. In an unusual decarboxylation mechanism, the resulting aminomethyl moiety is instead transferred to an accessory H-protein. This study defines the role of H-protein in GLDC-catalyzed glycine decarboxylation. (1) H-Protein is not required for glycine decarboxylation but, instead, is required for the release of the aminomethyl moiety from the quinonoid adduct. (2) Glycine decarboxylation is reversible and presumably proceeds through a stable quinonoid intermediate. (3) The physiological product of glycine decarboxylation is H-protein-S-aminomethyl dihydrolipoyllysine and not methylamine (in the absence of H-protein, the aminomethyl moiety remains as a quinonoid adduct). Mechanistic insights obtained from this study will inform future efforts for targeted anticancer therapeutic development.
Department of Biochemistry, Yong Loo Lin School of Medicine, National University of Singapore , 8 Medical Drive, Singapore 117597.
Maybelle Kho
MK
Go
Wen Cai
WC
Zhang
Bing
B
Lim
Wen Shan
WS
Yew
D063646:Carcinogenesis / Q000378:metabolism*; D002384:Catalysis; D005998:Glycine / Q000737:chemistry; D050961:Glycine Decarboxylase Complex H-Protein / Q000737:chemistry / Q000378:metabolism; D050841:Glycine Dehydrogenase (Decarboxylating) / Q000737:chemistry* / Q000378:metabolism; D006801:Humans; D007700:Kinetics
D050961:Glycine Decarboxylase Complex H-Protein; D050841:Glycine Dehydrogenase (Decarboxylating); D005998:Glycine