Metabolic pathways are often considered "perfected" or at least predictable as substrates efficiently rearrange into products through the intervention of an optimized enzyme. Moreover, single catalytic steps link up, forming a myriad of metabolic circuits that are often modeled with a high degree of certainty. However, on closer examination, most enzymes are not precise with respect to their activity, using not just one substrate but often a variety and producing not just one product but a diversity. Hence, the metabolic systems assembled from enzymes possessing varying degrees of what can be termed catalytic promiscuity are not clear-cut and restrictive; rather, they may at times operate stochastically in the intracellular milieu. This "messiness" complicates our understanding of normal and aberrant cellular behavior, while paradoxically sowing the seeds for future advantageous metabolic adaptations for host organisms. Catalytic promiscuity is intrinsically associated with the dynamic nature of enzyme structures and their chemical mechanisms, both key to enzyme and metabolic evolvability. In addition to primary (core) metabolism, which is essential for survival, organisms also possess highly elaborated secondary (specialized) metabolic systems. These specialized enzymes and pathways often provide unique adaptive strategies for a myriad of organisms and their populations in challenging and changing ecosystems. Generally, enzymes of specialized metabolism show attenuated kinetic activities and expanded catalytic promiscuity compared with their phylogenetic relatives rooted in primary metabolism. We propose that evolvability may be a selected trait in many specialized metabolic systems spread across populations of organisms exposed to continually fluctuating biotic and abiotic environmental pressures. As minor metabolites arising from catalytic messiness provided enhanced population fitness, specificity relaxed, and catalytic efficiency was attenuated. This updated view provides a mechanistic basis for reaching a deeper understanding of the evolutionary underpinnings of the explosion of chemodiversity in nature.
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