Pyridoxal phosphate

Comparison of the catalysis of ThDP-dependent enzymes AHAS, ALS, and DXPS.[Pubmed:42805693]

Methods Enzymol. 2026;736:127-156.

Thiamine diphosphate (ThDP)-dependent enzymes are primarily classified into lyases, transferases, and oxidoreductases, catalyzing various biologically important reactions such as keto transfer, dehydrogenation, decarboxylation, and stereoselective C-C bond formation/cleavage in chiral natural products biosynthesis. They constitute one of the largest superfamilies of biocatalysts, operate basically in all forms of living systems. In this chapter, the research progress on three ThDP enzymes are reviewed, including acetohydroxyacid synthase (AHAS) which is a key enzyme in the anabolic pathway for the biosynthesis of branched chain amino acids, acetolactate synthase (ALS) that belongs to the catabolic pathway for the biosynthesis of platform compounds acetoin and 2,3-butanediol, and 1-deoxy-D-xylulose-5-phosphate synthase (DXPS) which is a rate-limiting enzyme in the MEP terpenoid biosynthetic pathway and is also involved in the biosynthesis of ThDP and Pyridoxal phosphate in certain bacteria, with the emphasis on comparing the catalysis of the three enzymes. Furthermore, two precolumn derivatization-HPLC protocols using 4-nitro-o-phenylenediamine and 2,4-dinitrophenylhydrazine as respective derivatizing reagents are also described in detail. The methods can not only be utilized to measure the activities of the above enzymes, supplementing the deficiencies of the classic spectrophotometry, but also be used to comprehensively elucidate the consumption of the substrate(s) and the formation of the products in the reactions catalyzed by AHAS, ALS, or DXPS.

Cycloserine inhibits glutamate decarboxylase from Mycobacterium tuberculosis.[Pubmed:42765272]

J Enzyme Inhib Med Chem. 2026 Dec;41(1):2707854.

Glutamate decarboxylase (GadB) is a Pyridoxal phosphate (PLP)-dependent enzyme that contributes to intracellular pH homeostasis and supports the survival of Mycobacterium tuberculosis (Mtb) in lung tissue, granulomas, and within host macrophages. Here, we demonstrate that glutamate decarboxylase from Mycobacterium tuberculosis (MtbGadB) is a multimeric enzyme exhibiting maximal activity under acidic conditions. MtbGadB is inhibited by the clinical antibiotic d-cycloserine as well as l-cycloserine in vitro. Both cycloserine enantiomers break the internal aldimine bond between PLP and the conserved Lys277 residue, forming a previously unrecognised PLP-oxime product and subsequently inhibiting catalysis. Given that PLP-dependent enzymes are promising drug targets, understanding the chemical behaviour of PLP is essential for developing selective inhibitors.

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