Crystal structure of thiamin pyrophosphokinase

David E. Timm, Jingyuan Liu, L. J. Baker, Robert Harris

Research output: Contribution to journalArticle

34 Citations (Scopus)

Abstract

Thiamin pyrophosphate (TPP) is a coenzyme derived from vitamin B1 (thiamin). TPP 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 Å resolution, and the structure of TPK complexed with thiamin has been refined at 1.9 Å resolution. The TPK polypeptide folds as an α/β-domain and a β-sandwich domain, which share a central ten-stranded mixed β-sheet. TPK subunits associate as a dimer, and thiamin is bound in the dimer interface. Despite lacking apparent sequence homology with other proreins, the α/β-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.

Original languageEnglish
Pages (from-to)195-204
Number of pages10
JournalJournal of Molecular Biology
Volume310
Issue number1
DOIs
StatePublished - Jun 29 2001

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Thiamin Pyrophosphokinase
Thiamine
Thiamine Pyrophosphate
Beriberi
Wernicke Encephalopathy
Acetyl Coenzyme A
Citric Acid Cycle
Coenzymes
Sequence Homology
Anti-Infective Agents
Eukaryota
Phosphotransferases
Adenosine Triphosphate
Yeasts
Glucose

Keywords

  • Crystal structure
  • Kinase
  • Metabolism
  • Thiamin
  • Vitamin

ASJC Scopus subject areas

  • Virology

Cite this

Crystal structure of thiamin pyrophosphokinase. / Timm, David E.; Liu, Jingyuan; Baker, L. J.; Harris, Robert.

In: Journal of Molecular Biology, Vol. 310, No. 1, 29.06.2001, p. 195-204.

Research output: Contribution to journalArticle

Timm, David E. ; Liu, Jingyuan ; Baker, L. J. ; Harris, Robert. / Crystal structure of thiamin pyrophosphokinase. In: Journal of Molecular Biology. 2001 ; Vol. 310, No. 1. pp. 195-204.
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