The guanidino-group modifying enzymes

Structural basis for their diversity and commonality

Hiroki Shirai, Younes Mokrab, Kenji Mizuguchi

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

The guanidino-group modifying enzyme (GME) superfamily contains many drug targets, including metabolic enzymes from pathogenic microorganisms as well as key regulatory proteins from higher eukaryotes. These enzymes, despite their diverse sequences, adopt the common α/β propeller fold and catalyze the modification of (methylated) guanidino groups. Our structural superposition and structure-based alignment for the GMEs have identified key residues that are involved in the catalysis and substrate binding. We have shown that conserved guanidino-carboxyl interactions are utilized in two different ways; the acidic residues in the catalytic site form hydrogen bonds to the substrate guanidino group, and the enzyme Arg residues at several key positions recognize the carboxyl group of the substrate and fix its orientation. Based on this observation, we have proposed rules for classifying the GME sequences and predicting their molecular function from the conservation of the key acidic and Arg residues. Other novel motifs have been identified, which involve residues that are not in direct contact with the substrate but are likely to stabilize the active-site conformation through hydrogen-bonding networks. In addition, we have examined the domain architecture of the GMEs. Although most members consist of a single catalytic domain, fold recognition analysis has identified a likely bifunctional enzyme from a cyanobacterium. It has also revealed common immunoglobulin-like β-sandwich domains found in the enzymes that recognize protein substrates. These findings will be useful for predicting the precise mechanism of action for potential novel targets and designing therapeutic compounds against them.

Original languageEnglish
Pages (from-to)1010-1023
Number of pages14
JournalProteins: Structure, Function and Genetics
Volume64
Issue number4
DOIs
Publication statusPublished - 1 Sep 2006
Externally publishedYes

Fingerprint

Enzymes
Substrates
Catalytic Domain
Hydrogen bonds
Cyanobacteria
Propellers
Hydrogen Bonding
Eukaryota
Catalysis
Microorganisms
Action Potentials
Conformations
Immunoglobulins
Hydrogen
Conservation
Proteins
Pharmaceutical Preparations
Therapeutics

Keywords

  • α/β propeller
  • Catalytic reaction
  • Enzyme mechanism
  • Fold recognition
  • Structure-based alignment

ASJC Scopus subject areas

  • Genetics
  • Structural Biology
  • Biochemistry

Cite this

The guanidino-group modifying enzymes : Structural basis for their diversity and commonality. / Shirai, Hiroki; Mokrab, Younes; Mizuguchi, Kenji.

In: Proteins: Structure, Function and Genetics, Vol. 64, No. 4, 01.09.2006, p. 1010-1023.

Research output: Contribution to journalArticle

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