Research: Asparagine Synthetase Deficiency;
Nutrient control of transcription
Ph.D. from University of South Dakota, 1977
Office: R3-116 ARB
Lab: R3-148 ARB
Telephone: (352) 294-8388
Professor Michael S. Kilberg earned his Ph.D. in biochemistry and molecular biology. He did post-doctoral studies at the University of Michigan, before joining the faculty at UF. He has written numerous reviews, organized several symposia, and written multiple chapters for both the Annual Review of Nutrition and the Annual Review of Biochemistry. Dr. Kilberg has served three terms on the Editorial Board of the Journal of Biological Chemistry. Dr. Kilberg has received the University of Florida Doctoral Advisor/Mentoring Award, the College of Medicine Faculty Research Award, and a University of Florida Research Foundation Professorship.
Asparagine synthetase (ASNS) catalyzes the ATP-dependent synthesis of asparagine (Asn) from aspartate, using glutamine (Gln) as the source of the amide nitrogen. The human ASNS enzyme has 561 AA residues, a predicted mass of 64.37 kDa, and two primary catalytic domains. The N-terminal domain (residues 1-208) contains the Gln hydrolysis site and the C-terminal domain (residues 209-561) binds ATP and aspartate to generate the aspartyl-AMP intermediate. Ammonia is transferred between the domains to generate the Asn product. Given the wide spread ASNS expression in human tissues, Asn is not considered a dietary essential amino acid (AA), but insufficient ASNS activity causes individual cells, tissues, or organs to become Asn-dependent. For example, standard multi-drug therapy of childhood acute lymphoblastic leukemia (ALL) includes Asparaginase (ASNase) because ALL cells lack sufficient ASNS to maintain growth in the absence of extracellular Asn. Research from our laboratory and others has revealed an inverse correlation between ASNase sensitivity and ASNS protein expression in ALL, ovarian cancer, and hepatocellular carcinoma. In 2013, a new inborn error of metabolism was discovered, Asparagine Synthetase Deficiency (ASNSD). ASNSD is associated with homozygous or compound heterozygous mutations within the human ASNS gene on chromosome 7q21.3, but the exact mechanisms that cause the overt symptoms of the disease are not well understood. Typically, newborns with this disease exhibit severe microcephaly that continues as progressive brain atrophy, intractable epileptic seizures, suppressed mental and physical development, and a shortened lifespan. Exome sequencing of children with these symptoms is the primary mechanism of diagnosis because there is no convenient, reproducible, and specific assay for ASNS enzymatic activity. Furthermore, conclusive evidence that particular ASNS mutations account totally for the phenotype and the degree to which specific ASNS variants function within cells remains unknown. Thus, there are critical gaps in our knowledge of ASNS function and the manifestation of ASNSD. Our research proposes to address these gaps by utilizing a new ASNS enzymatic assay and genomic approaches to provide further insight into the cellular impact of specific ASNSD-associated AA variants.