Crystal structure of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase, a potential target for the development of novel antimicrobial agents

Citation
B. Xiao et al., Crystal structure of 6-hydroxymethyl-7,8-dihydropterin pyrophosphokinase, a potential target for the development of novel antimicrobial agents, STRUCT F D, 7(5), 1999, pp. 489-496
Citations number
32
Categorie Soggetti
Biochemistry & Biophysics
Journal title
STRUCTURE WITH FOLDING & DESIGN
ISSN journal
09692126 → ACNP
Volume
7
Issue
5
Year of publication
1999
Pages
489 - 496
Database
ISI
SICI code
0969-2126(199905)7:5<489:CSO6PA>2.0.ZU;2-7
Abstract
Background: Folate cofactors are essential for life. Mammals derive folates from their diet, whereas most microorganisms must synthesize folates de no vo. Enzymes of the folate pathway therefore provide ideal targets for the d evelopment of antimicrobial agents, 6-Hydroxymethyl-7,8-dihydropterin pyrop hosphokinase (HPPK) catalyzes the transfer of pyrophosphate from ATP to 6-h ydroxymethyl-7,8-dihydropterin (HP), the first reaction in the folate biosy nthetic pathway. Results: The crystal structure of HPPK from Escherichia coli has been deter mined at 1.5 Angstrom resolution with a crystallographic R factor of 0.182. The HPPK molecule has a novel three-layered alpha beta alpha fold that cre ates a valley approximately 26 Angstrom long, 10 Angstrom wide and 10 Angst rom deep, The active center of HPPK is located in the valley and the substr ate-binding sites have been identified with the aid of NMR spectroscopy. Th e HP-binding site is located at one end of the valley, near Asn55, and is s andwiched between two aromatic sidechains. The ATP-binding site is located at the other end of the valley. The adenine base of ATP is positioned near Leu111 and the ribose and the triphosphate extend across and reach the vici nity of HP. Conclusions: The HPPK structure provides a framework to elucidate structure /function relationships of the enzyme and to analyze mechanisms of pyrophos phoryl transfer. Furthermore, this work may prove useful in the structure-b ased design of new antimicrobial agents.