Non-enzymatic molecular damage as a prototypic driver of aging

Abstract

The chemical potentialities of metabolites far exceed metabolic requirements. The required potentialities are realized mostly through enzymatic catalysis. The rest are realized spontaneously through organic reactions that (i) occur wherever appropriate reactants come together, (ii) are so typical that many have proper names (e.g. Michael addition, Amadori rearrangement, and Pictet-Spengler reaction), and (iii) often have damaging consequences. There are many more causes of non-enzymatic damage to metabolites than reactive oxygen species and free radical processes (the "usual suspects"). Endogenous damage accumulation in non-renewable macromolecules and spontaneously polymerized material is sufficient to account for aging and differentiates aging from wear-and-tear of inanimate objects by deriving it from metabolism, the essential attribute of life.

Keywords: aging; damage; enzyme; enzyme mechanism; mechanism; metabolism; metabolite; metabolite damage; side reaction; side-product; spontaneous chemistry; substrate specificity.

Figure 1.

Examples of non-enzymatic synthesis of complex compounds from simpler metabolites via Schiff base formation followed by double-to-single carbon-nitrogen bond conversion. The starting reactive moieties are highlighted with thick bonds and bold characters. Any other metabolically relevant structure or atom may replace a non-highlighted part, including phosphatidyl (indicated by Ptd in A and B). A, ribose exemplifies any monosaccharide. The amino group may be on a phospholipid (23), an amino acid (24), or a nucleic base (25), either free or included in a biopolymer, which may become cross-linked by such modification. B, see “Physiological implications of endogenous chemical damage” for comments. See Refs. and . C, tryptamine exemplifies any indoleamine, and pyruvate represents any carbonyl-containing compound, including saccharides. With catecholamines instead of indoleamines, the Pictet-Spengler reaction yields tetrahydroisoquinolines, whose neurotoxicity is implicated in brain aging (16, 17). Figures were drawn using MarvinSketch 16.5.2.0 (ChemAxon).

Figure 2.

Examples of non-enzymatic synthesis of complex compounds from simpler metabolites without Schiff base involvement. See Fig. 1 for general comments. A, dopamine exemplifies any catecholamine. Quinone formation is possible without oxygen involvement, being driven by ferric iron reduction (28). Cysteine may be a free amino acid or a part of glutathione or protein. 5-S-Cysteinyl dopamine is mostly protein-bound, whereas the free cysteine gives rise to cytotoxic dihydrobenzothiazine derivatives (18, 29). B, carbamylation of any amino-group bearer is possible. Only the homocitrulline level in human skin has been shown so far to increase with age (30). C, high reactivity of thioesters is long acknowledged in chemistry. Their ability to acylate cellular proteins non-enzymatically is reported in several recent publications (20, 31, 32).