Steve Ealick's Research Group


Candida albicans THI5p


PDB files:

4ESW H66G mutant

4ESX wild type complexed with PLP

Description:

In yeast the thiazole and pyrimidine heterocycles are joined for form thiamin are biosynthesized using chemistry that is different from the bacterial pathway. In bacteria, the thiazole is formed from deoxy-D-xylulose 5-phosphate, glycine (or tyrosine), and cysteine, and the pyrimidine is formed from aminoimidazole ribotide. In yeast pyrimidine is formed from histidine and pyridoxal phosphate (PLP). 4-amino-2-methyl-5-hydroxymethylpyrimidine phosphate (HMP-P) is formed using remarkable chemistry that is without chemical or biochemical precedent and requires only a single gene (THI5). We deteremined the structure of Candida albicans THI5p (CaTHI5p), which is the histidine source for HMP-P formation and is also a single-turnover enzyme. CaTHI5p belongs to the group II periplasmic binding protein (PBP) family with its closes structural homologue ThiY.

Each protomer of CaTHI5p is characterized by two globular αβα domains connected by two crossovers. The bound PLP is shown in the active site.

 


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In the crystal structure, the protomers are packed as a dimer with considerable contact at the interface.


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THI5p showing PLP bound via an imine to Lys62 and His66 in close proximity to the PLP.


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Reference:

Lai RY, Huang S, Fenwick MK, Hazra AB, Zhang Y, Rajashankar KR, Philmus B, Kinsland C, Sanders JM, Ealick SE, and Begley TP. Thiamin pyrimidine biosynthesis in Candida albicans: a remarkable reaction between histidine and pyridoxal phosphate. J. Am. Chem. Soc. 134:9157−9159. (2012). PubMed



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