A mathematical genomics perspective on the moonlighting role of glyceraldehyde-3-phosphate dehydrogenase (GAPDH)

Article Type

Research Article

Publication Title

International Journal of Biological Macromolecules

Abstract

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a highly conserved enzyme across Archaea, Bacteria, and Eukarya, known for its canonical role in glycolysis and diverse moonlighting functions in transcription regulation, host–pathogen interactions, and immune modulation. To investigate how sequence-level variation contributes to this functional versatility, we performed a comparative analysis of 165 GAPDH proteins from 158 species using a diverse suite of computational descriptors. By integrating amino acid composition, poly-string profiling, polarity transition patterns, intrinsic disorder propensity, and fractal spatial metrics, we present a comprehensive quantitative framework for examining GAPDH evolution. Our results show that while core catalytic residues are strongly preserved, selective enrichment of small nonpolar residues (valine, alanine) and a balanced distribution of order- and disorder-promoting residues support both structural stability and regulatory flexibility. These findings suggest that GAPDH multifunctionality arises from a composite of conserved and divergent sequence signatures. Unlike previous single-parameter studies, this work introduces a unified, multi-parametric strategy that uncovers hidden evolutionary patterns and offers a generalizable framework for decoding moonlighting behavior in proteins. Beyond reinforcing known aspects of GAPDH biology, this integrative analysis positions GAPDH as a model for exploring broader principles of protein multifunctionality and highlights the power of quantitative profiling in revealing hidden functional layers.

DOI

10.1016/j.ijbiomac.2025.148045

Publication Date

11-1-2025

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