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Biological Chemistry; Center for Human Nutrition (JHSPH) Oncology Center
707 N. Broadway
Kennedy Krieger Institute, Rm 400G
Baltimore MD 21205
Fatty Acid Activation Enzymes
My laboratory's primary interest is fatty acid metabolism in inherited metabolic diseases and in cancer. X-linked adrenoleukodystrophy (XALD) and peroxisomal biogenesis disorders are characterized biochemically by having excess very long-chain fatty acids (VLCFA, containing 26 or more carbons) in tissue lipids. High VLCFA levels are thought to contribute to the neurologic deficits and other pathophysiologic processes seen in these diseases. A recent focus of the lab is to identify and characterize small molecules that lower VLCFA levels in cells from XALD patients, and in a mouse model of the disease. All fatty acids 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. The “very long-chain” acyl-CoA synthetase family contains 6 members. We found that the expression of one member of this family, ACSVL3, is significantly increased in human brain and lung cancer. Knocking out 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. We are testing several compounds that were reported to inhibit ACSVL1, a close relative of ACSVL3, for their anti-cancer potential. In addition, we have developed a high-throughput screening assay to identify more drugs that inhibit ACSVL3.
Pei Z, Sun P, Huang P, Lal B, Laterra J, and Watkins PA (2009) ACSVL3 depletion decreases the malignant phenotype of human gliomas. Cancer Res. 69, 9175-9182.
Watkins PA (2008) Very long-chain acyl-CoA synthetases. J. Biol. Chem. 283, 1773-1777.
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.
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.
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.