The crystal structure of the bifunctional enzyme 6-phosphofructo-2- kinase/fructose-2,6-bisphosphatase reveals distinct domain homologies

Charles A. Hasemann, Eva S. Istvan, Kosaku Uyeda, Johann Deisenhofer

Research output: Contribution to journalArticle

114 Scopus citations

Abstract

Background: Glucose homeostasis is maintained by the processes of glycolysis and gluconeogenesis. The importance of these pathways is demonstrated by the severe and life threatening effects observed in various forms of diabetes. The bifunctional enzyme 6-phosphofructo-2- kinase/fructose-2,6-bisphosphatase catalyzes both the synthesis and degradation of fructose-2,6-bisphosphate, a potent regulator of glycolysis. Thus this bifunctional enzyme plays an indirect yet key role in the regulation of glucose metabolism. Results: We have determined the 2.0 Å crystal structure of the rat testis isozyme of this bifunctional enzyme. The enzyme is a homodimer of 55 kDa subunits arranged in a head-to-head fashion, with each monomer consisting of independent kinase and phosphatase domains. The location of ATPγS and inorganic phosphate in the kinase and phosphatase domains, respectively, allow us to locate and describe the active sites of both domains. Conclusions: The kinase domain is clearly related to the superfamily of mononucleotide binding proteins, with a particularly close relationship to the adenylate kinases and the nucleotide-binding portion of the G proteins. This is in disagreement with the broad speculation that this domain would resemble phosphofructokinase. The phosphatase domain is structurally related to a family of proteins which includes the cofactor independent phosphoglycerate mutases and acid phosphatases.

Original languageEnglish (US)
Pages (from-to)1017-1029
Number of pages13
JournalStructure
Volume4
Issue number9
DOIs
StatePublished - Sep 15 1996

Keywords

  • X-ray crystallography
  • bifunctional enzyme
  • phosphoric monoester hydrolase
  • phosphotransferase
  • protein structure

ASJC Scopus subject areas

  • Structural Biology
  • Molecular Biology

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