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CysG structure reveals tetrapyrrole-binding features and novel regulation of siroheme biosynthesis

Academic Article
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Overview

related to degree

  • Stroupe, Margaret, Ph.D. in Biology, Scripps Research 1997 - 2002

authors

  • Stroupe, Margaret
  • Leech, H. K.
  • Daniels, Douglas
  • Warren, M. J.
  • Getzoff, Elizabeth

publication date

  • December 2003

journal

  • Nature Structural Biology  Journal

abstract

  • Sulfur metabolism depends on the iron-containing porphinoid siroheme. In Salmonella enterica, the S-adenosyl-L-methionine (SAM)-dependent bismethyltransferase, dehydrogenase and ferrochelatase, CysG, synthesizes siroheme from uroporphyrinogen III (uro'gen III). The reactions mediated by CysG encompass two branchpoint intermediates in tetrapyrrole biosynthesis, diverting flux first from protoporphyrin IX biosynthesis and then from cobalamin (vitamin B(12)) biosynthesis. We determined the first structure of this multifunctional siroheme synthase by X-ray crystallography. CysG is a homodimeric gene fusion product containing two structurally independent modules: a bismethyltransferase and a dual-function dehydrogenase-chelatase. The methyltransferase active site is a deep groove with a hydrophobic patch surrounded by hydrogen bond donors. This asymmetric arrangement of amino acids may be important in directing substrate binding. Notably, our structure shows that CysG is a phosphoprotein. From mutational analysis of the post-translationally modified serine, we suggest a conserved role for phosphorylation in inhibiting dehydrogenase activity and modulating metabolic flux between siroheme and cobalamin pathways.

subject areas

  • Amino Acid Sequence
  • Binding Sites
  • Crystallography, X-Ray
  • Heme
  • Methyltransferases
  • Models, Molecular
  • Molecular Sequence Data
  • Phosphoproteins
  • Phosphoserine
  • Protein Conformation
  • Tetrapyrroles
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Identity

International Standard Serial Number (ISSN)

  • 1072-8368

Digital Object Identifier (DOI)

  • 10.1038/nsb1007

PubMed ID

  • 14595395
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Additional Document Info

start page

  • 1064

end page

  • 1073

volume

  • 10

issue

  • 12

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