My laboratory's primary interest is fatty acid metabolism. Fatty acids, from the shortest 2-carbon acid to the very long-chain fatty acids (VLCFA) containing 26 or more carbons, must be activated to their coenzyme A thioester before participating in metabolic processes. Using bioinformatics approaches and data from genome sequencing projects, we determined that humans and mice have ~26 different enzymes that catalyze this reaction—the acyl-CoA synthetases. Conserved motifs in their amino acid sequences have allowed us to classify them into families of related proteins. Although we know a bit about the fatty acid chain-length specificity of the acyl-CoA synthtases, their tissue expression patterns, and perhaps their subcellular location, we know little about the precise function of each enzyme. Our hypothesis is that the ACSs not only activate fatty acids but also direct them toward a specific metabolic fate in a specific compartment of the cell.

Two “families” of acyl-CoA synthetases are the subjects of current research. One is the “very long-chain” acyl-CoA synthetase family, which contains 6 members. We found that the expression of one member of this family is significantly increased in human brain and lung cancer. Knocking down this enzyme in human glioblastoma cells decreases their malignant behavior in vitro, and decreases their ability to produce tumors in mice. The role of this enzyme in cancer cells with respect to lipid metabolism and signal transduction pathways is an area of active investigation.

The “bubblegum” family, named for a fruitfly mutant, has 2 members. One member is of interest because the enzyme is only found in neurons and in steroidogenic cells of the adrenal glands and testes, precisely the cell types affected pathologically in the peroxisomal disease X-linked adrenoleukodystrophy (ALD). New studies have begun to shed light on the regulation of this enzyme, and suggest a role for it in the synthesis of sphingolipids and in GABAA receptor function. The second “bubblegum” family member is only found in testicular Sertoli cells and in large motorneurons of the brainstem. We are investigating a possible role for this enzyme in male fertility, and perhaps in amyotrophic lateral sclerosis (Lou Gherig’s disease).

Publications:

Pei Z, Jia Z, and Watkins PA (2006) The second member of the human and murine “bubblegum” family is a testis- and brainstem-specific acyl-CoA synthetase. J. Biol. Chem. 281, 6632-6641.
PubMed Reference

Jia Z, Moulson CL, Pei Z, Miner JH, and Watkins PA (2007) FATP4 is the principal very long-chain fatty acyl-CoA synthetase in skin fibroblasts. J. Biol. Chem. 282, 20573-20583.PubMed Reference

Watkins PA, Maiguel D, and Jia Z (2007) Evidence for 26 distinct acyl-CoA synthetase genes in the human genome. J. Lipid Res. 48, 2736-2750.PubMed Reference

Watkins PA (2008) Very long-chain acyl-CoA synthetases. J. Biol. Chem. 283, 1773-1777.PubMed Reference