1.7 ANGSTROM RESOLUTION CRYSTAL STRUCTURE OF 6-HYDROXYMETHYL-7,8-DIHYDROPTEROATE SYNTHASE (DHPS) FROM MYCOBACTERIUM TUBERCULOSIS IN COMPLEX WITH 6-HYDROXYMETHYLPTERIN MONOPHOSPHATE1.7 ANGSTROM RESOLUTION CRYSTAL STRUCTURE OF 6-HYDROXYMETHYL-7,8-DIHYDROPTEROATE SYNTHASE (DHPS) FROM MYCOBACTERIUM TUBERCULOSIS IN COMPLEX WITH 6-HYDROXYMETHYLPTERIN MONOPHOSPHATE
Structural highlights
1eye is a 1 chain structure with sequence from Mycobacterium tuberculosis H37Rv. Full crystallographic information is available from OCA. For a guided tour on the structure components use FirstGlance.
DHPS1_MYCTU Catalyzes the condensation of para-aminobenzoate (pABA) with 6-hydroxymethyl-7,8-dihydropterin diphosphate (DHPt-PP) to form 7,8-dihydropteroate (H2Pte), the immediate precursor of folate derivatives.[1][2][3] Is involved in the bioactivation of the antituberculous drug para-aminosalicylic acid (PAS). PAS is a close structural analog of pABA and acts as an alternative substrate for DHPS, leading to hydroxy-dihydropteroate (H2PtePAS). Metabolomic studies show that PAS, despite its in vitro activity as a competitive inhibitor of DHPS, does not inhibit growth of M.tuberculosis by inhibiting DHPS. PAS exerts its antimycobacterial activity through its effects on M.tuberculosis folate metabolism downstream of DHPS. PAS poisons folate-dependent pathways not only by serving as a replacement substrate for DHPS but also by the products of that reaction serving as replacement substrates and/or inhibitors of subsequent enzymes.[4][5]
Evolutionary Conservation
Check, as determined by ConSurfDB. You may read the explanation of the method and the full data available from ConSurf.
↑Nopponpunth V, Sirawaraporn W, Greene PJ, Santi DV. Cloning and expression of Mycobacterium tuberculosis and Mycobacterium leprae dihydropteroate synthase in Escherichia coli. J Bacteriol. 1999 Nov;181(21):6814-21. PMID:10542185 doi:10.1128/JB.181.21.6814-6821.1999
↑Chakraborty S, Gruber T, Barry CE 3rd, Boshoff HI, Rhee KY. Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis. Science. 2013 Jan 4;339(6115):88-91. PMID:23118010 doi:10.1126/science.1228980
↑Zheng J, Rubin EJ, Bifani P, Mathys V, Lim V, Au M, Jang J, Nam J, Dick T, Walker JR, Pethe K, Camacho LR. para-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis. J Biol Chem. 2013 Aug 9;288(32):23447-56. PMID:23779105 doi:10.1074/jbc.M113.475798
↑Chakraborty S, Gruber T, Barry CE 3rd, Boshoff HI, Rhee KY. Para-aminosalicylic acid acts as an alternative substrate of folate metabolism in Mycobacterium tuberculosis. Science. 2013 Jan 4;339(6115):88-91. PMID:23118010 doi:10.1126/science.1228980
↑Zheng J, Rubin EJ, Bifani P, Mathys V, Lim V, Au M, Jang J, Nam J, Dick T, Walker JR, Pethe K, Camacho LR. para-Aminosalicylic acid is a prodrug targeting dihydrofolate reductase in Mycobacterium tuberculosis. J Biol Chem. 2013 Aug 9;288(32):23447-56. PMID:23779105 doi:10.1074/jbc.M113.475798
