S-Adenosyl-L-Homocysteine Hydrolase (SAHH): Structure, Function, and Applications

S-adenosyl-L-homocysteine hydrolase (SAHH) is an evolutionarily conserved enzyme present in eukaryotes, bacteria, and archaea. As the rate-limiting enzyme in the methionine cycle, it catalyzes the reversible hydrolysis of S-adenosyl-L-homocysteine (SAH) to adenosine and homocysteine, thereby modulating the S-adenosylmethionine/SAH ratio and cellular methylation potential. Dysregulation of SAHH activity is causally linked to cancer, cardiovascular disorders, and neurodegenerative conditions. This review systematically examines the biological distribution, catalytic mechanisms, structural architecture, and regulation of SAHH across diverse species. We highlight lineage-specific adaptations—including C-terminal truncation, a 40-residue substrate-binding-domain insertion, and a His-Phe molecular gate—that fine-tune substrate preference, cofactor affinity, and thermostability, with metal ions and NAD+ serving as key modulators of activity and conformational dynamics. These variations exemplify an evolutionary trade-off between catalytic efficiency and structural rigidity, particularly pronounced in archaeal and thermophilic orthologs. Collectively, these insights underpin the enzyme’s multifaceted translational value: SAHH serves as a therapeutic target for diverse diseases (e.g., cancer, viral infections, tuberculosis), a source of diagnostic/prognostic biomarkers (e.g., plasma homocysteine and SAH/SAM ratio), and a versatile biocatalyst for synthesizing pharmaceutical-grade adenosine and its derivatives. By integrating mechanistic, structural, and evolutionary perspectives, this review establishes a unified framework that explains these functional adaptations and their translational implications. This framework guides the rational development of SAHH-targeted inhibitors, diagnostic tools, and engineered biocatalysts, with broad applications in precision medicine and biotechnology.