The return of metabolism: biochemistry and physiology of glycolysis

Glycolysis is a fundamental metabolic pathway central to the bioenergetics and physiology of virtually all living organisms. In this comprehensive review, we explore the intricate biochemical principles and evolutionary origins of glycolytic pathways, from the classical Embden-Meyerhof-Parnas (EMP) pathway in humans to various prokaryotic and alternative glycolytic routes. By examining glycolysis across the tree of life, we explore its presence and adaptation in prokaryotes, archaea, bacteria, animals and plants, and the extension of glycolysis into sulfosugar metabolism. Further, we discuss the role of unwanted side reactions, thermodynamic principles, and metabolic control principles that underpin glycolysis and the broader metabolic network, and summarise advanced methods for quantifying glycolytic activity, including new analytical methods, alongside kinetic, constraint-based, and machine-learning based modelling. With a focus on the Pasteur, Crabtree, and Warburg effects, this review further discusses the roles of glycolysis in health and disease, highlighting its impact on global metabolic operations, inborn errors, and various pathologies as well as its role in biotechnology and metabolic engineering.