Cost-saving, trading, and internalization of externality: three economic strategies underlying amino acid archetypes of human metabolic enzymes

Amino acid composition of proteome reflects principles of metabolic resource allocation. While amino acids with higher biosynthetic costs are used less frequently in unicellular organisms, whether this rule extends to complex multicellular life remains elusive. Here we show that amino acid composition of human metabolic enzymes does not follow a simple cost-minimizing mode but instead segregate into four distinct amino-acid composition modules each associated with specific metabolic functions, a phenomenon we term emergence of amino acid archetypes (AArchetypes). By comparing ten phylogenetically diverse species, we find that AArchetypes emerge only in multicellular organisms, indicating a fundamental shift in proteome-level economics. We further demonstrate that these AArchetypes correspond to three distinct economic strategies: cost-saving in young, fast-evolving enzymes; trading in conserved central carbon metabolic enzymes whose amino-acid compositions match that of dietary intake; and internalization of negative externalities in liquid-liquid phase separation (LLPS)-prone, intrinsically disordered proteins through elevated biosynthetic costs of LLPS-associated amino acids. Together, these results reveal that multicellular proteomes are governed not by a single cost-minimization principle, but by a multi-layered economic system that integrates production, exchange, and regulation.