The guanidino-group modifying enzymes: structural basis for their diversity and commonality

Area of Science:

• Biochemistry
• Structural Biology
• Enzymology

Background:

• The guanidino-group modifying enzyme (GME) superfamily comprises diverse proteins with a conserved alpha/beta propeller fold.
• These enzymes are crucial drug targets, involved in microbial metabolism and eukaryotic regulation.
• GMEs catalyze the modification of guanidino groups, a key biochemical reaction.

Purpose of the Study:

• To elucidate the conserved structural and catalytic features of the GME superfamily.
• To develop a classification system for GME sequences and predict their molecular functions.
• To identify novel motifs and domain architectures within GMEs for therapeutic targeting.

Main Methods:

• Structural superposition and structure-based sequence alignment of GME superfamily members.
• Analysis of conserved guanidino-carboxyl interactions within the catalytic site.
• Fold recognition analysis to examine domain architecture and identify novel enzyme types.

Main Results:

• Identified key acidic and arginine residues critical for substrate binding and catalysis via conserved guanidino-carboxyl interactions.
• Established rules for classifying GME sequences and predicting function based on conserved residue patterns.
• Discovered novel stabilizing motifs and identified immunoglobulin-like beta-sandwich domains in protein-targeting GMEs.

Conclusions:

• Conserved interactions provide a basis for understanding GME function and classification.
• Structural insights facilitate the prediction of mechanisms for novel GME drug targets.
• Findings support the rational design of therapeutic compounds targeting the GME superfamily.