Crystal structure of thiamin pyrophosphokinase

被引:33
作者
Timm, DE [1 ]
Liu, JY [1 ]
Baker, LJ [1 ]
Harris, RA [1 ]
机构
[1] Indiana Univ, Sch Med, Dept Biochem & Mol Biol, Indianapolis, IN 46202 USA
关键词
thiamin; crystal structure; vitamin; metabolism; kinase;
D O I
10.1006/jmbi.2001.4727
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
Thiamin pyrophosphate (TPP) is a coenzyme derived from vitamin B-1 (thiamin). TTP synthesis in eukaryotes requires thiamin pyrophosphokinase (TPK), which catalyzes the transfer of a pyrophosphate group from ATP to thiamin. TPP is essential for central metabolic processes, including the formation of acetyl CoA from glucose and the Krebs cycle. Deficiencies in human thiamin metabolism result in beriberi and Wernicke encephalopathy. The crystal structure of mouse TPK was determined by multiwavelength anomalous diffraction at 2.4 Angstrom resolution, and the structure of TPK complexed with thiamin has been refined at 1.9 Angstrom resolution. The TPK polypeptide folds as an alpha/beta -domain and a beta -sandwich domain, which share a central ten-stranded mixed beta -sheet. TPK subunits associate as a dimer, and thiamin is bound in the dimer interface. Despite lacking apparent sequence homology with other proteins, the alpha/beta -domain resembles the Rossman fold and is similar to other kinase structures, including another pyrophosphokinase and a thiamin biosynthetic enzyme. Comparison of mouse and yeast TPK structures reveals differences that could be exploited in developing species-specific inhibitors of potential use as antimicrobial agents. (C) 2001 Academic Press.
引用
收藏
页码:195 / 204
页数:10
相关论文
共 36 条
[1]   HIGH-RESOLUTION STRUCTURES OF ADENYLATE KINASE FROM YEAST LIGATED WITH INHIBITOR AP(5)A, SHOWING THE PATHWAY OF PHOSPHORYL TRANSFER [J].
ABELE, U ;
SCHULZ, GE .
PROTEIN SCIENCE, 1995, 4 (07) :1262-1271
[2]  
AEvarsson A, 1999, NAT STRUCT BIOL, V6, P785
[3]   THE CCP4 SUITE - PROGRAMS FOR PROTEIN CRYSTALLOGRAPHY [J].
BAILEY, S .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1994, 50 :760-763
[4]   Crystallography & NMR system:: A new software suite for macromolecular structure determination [J].
Brunger, AT ;
Adams, PD ;
Clore, GM ;
DeLano, WL ;
Gros, P ;
Grosse-Kunstleve, RW ;
Jiang, JS ;
Kuszewski, J ;
Nilges, M ;
Pannu, NS ;
Read, RJ ;
Rice, LM ;
Simonson, T ;
Warren, GL .
ACTA CRYSTALLOGRAPHICA SECTION D-BIOLOGICAL CRYSTALLOGRAPHY, 1998, 54 :905-921
[5]   Crystal structure of 4-methyl-5-β-hydroxyethylthiazole kinase from Bacillus subtilis at 1.5 Å resolution [J].
Campobasso, N ;
Mathews, II ;
Begley, TP ;
Ealick, SE .
BIOCHEMISTRY, 2000, 39 (27) :7868-7877
[6]  
CHIU JJ, 1998, BIOCHEMISTRY-US, V38, P6460
[7]  
Eriksen TA, 2000, NAT STRUCT BIOL, V7, P303
[8]  
FANKHAUSER H, 1995, J BIOL CHEM, V270, P28457
[9]  
Giraud MF, 2000, NAT STRUCT BIOL, V7, P398
[10]  
GUBLER CJ, 1990, HDB VITAMINS