Evidence for at least 25 distinct acyl‐CoA synthetase genes in the human genome

Acyl‐CoA synthetases (ACS) catalyze the fundamental, initial reaction in fatty acid metabolism. By thioesterification to coenzyme A, fatty acids become “activated”, allowing their participation in both anabolic and catabolic pathways. The availability of the sequenced human genome has facilitated investigation of the number of ACS genes encoded. Two conserved amino acid sequence motifs are readily identifiable in known and putative ACSs. One is a very highly conserved AMP‐binding domain common to enzymes whose reaction mechanism involves an adenylated substrate intermediate. The second motif is more variable, but contains several highly conserved residues that form a consensus sequence. Using these two motifs to probe human genomic, non‐redundant, and EST databases, at least 25 candidate ACS genes/proteins were identified. All known ACSs were detected, and several previously undescribed genes were also found. Because of the diversity of acyl chain lengths encountered by cells, ACSs that differ in their chain‐length specificites have evolved; sequence similarities within the second conserved motif permit segregation of enzymes into families that roughly correspond to their acyl chain‐length preference. Additional candidate ACSs that do not readily fit into these families were also identified. Comparison of human ACS sequences to those of bacterial and yeast ACSs whose crystal structures have been solved revealed the presence of additional amino acid residues and motifs that likely have functional or structural roles. Knowing the full complement of ACS genes in the human genome should facilitate characterization of their metabolic functions. Supported by NIH grants NS37355, HD10981, and HD24061.