Enzyme promiscuity: engine of evolutionary innovation

Area of Science:

• Biochemistry
• Enzymology
• Molecular Evolution

Background:

• Enzyme evolvability is crucial for acquiring new biological functions.
• Substrate ambiguity, or action on multiple substrates, allows enzymes to perform diverse cellular roles.
• These roles include proofreading, nutrient scavenging, and metabolite pool balancing.

Purpose of the Study:

• To review enzymes that utilize substrate ambiguity for cellular functions.
• To present the structural features enabling both enzyme specificity and ambiguity.
• To focus on phosphatases from the haloalkanoate dehalogenase superfamily and thioesterases from the hotdog fold superfamily.

Main Methods:

• Literature review of enzymes exhibiting substrate ambiguity.
• Analysis of structural data for key enzyme superfamilies.
• Case studies focusing on haloalkanoate dehalogenases and hotdog fold thioesterases.

Main Results:

• Substrate ambiguity enables enzymes to perform essential cellular functions beyond single-metabolite catalysis.
• Specific structural motifs within enzyme active sites can accommodate multiple substrates while maintaining catalytic efficiency.
• Examples demonstrate how phosphatases and thioesterases leverage ambiguity for diverse biological roles.

Conclusions:

• Enzyme substrate ambiguity is a fundamental mechanism for biological innovation and cellular robustness.
• Understanding the structural basis of substrate ambiguity provides insights into enzyme evolution.
• The reviewed superfamilies serve as excellent models for studying the interplay between specificity and ambiguity in enzymes.