Ljubica Caldovic Ljubica Caldovic
Professor of Genomics and Precision Medicine
Professor of Pediatrics (Secondary)
Professor of Biochemistry and Molecular Medicine (Third)

Office Phone: 202-476-5819
Email: Email
Department: Genomics and Precision Medicine

Education

  • BS, University Belgrade, 1988
  • PhD, University of Minnesota, Minneapolis-St. Paul, 1997

Biography

How do proteins, nucleic acids, lipids and sugars come together to form cells, tissues and organisms? What guides the assembly of macromolecules and govern interactions among molecules that make living organisms? Do biological principles emerge from these chemical interactions? To find answers to these questions I have studied chemistry and biochemistry as an undergraduate student, molecular biology, genetics and biophysics both in graduate school and as a post-doc, and have been combining these disciplines throughout my scientific career. I chose to major in chemistry and biochemistry at the University of Belgrade because I wanted to know what living things were made of. I soon realized that understanding interactions among components of living organisms was even more interesting and exciting than their composition. This led me to study molecular biology and genetics in graduate school at the University of Minnesota. In graduate school, I studied the role of chromatin structure in the regulation of gene expression and overall organization of the cell nucleus by examining effects of chromatin insulators on expression of transgenes in zebrafish, Danio rerio. This led to realization that biological systems are complex systems with many interacting elements and refocused my research interests and projects to reflect my interest in experimental approaches for studying complex biological systems. I joined the lab of Professor Clare Woodward in the Biochemistry department of the University of Minnesota and worked on protein design because at that time, the study of protein folding and dynamics was the only area of biology with well established experimental methods to study a complex system such as the protein molecule as well as firm theoretical models of protein folding. During my second post-doc in the lab of Dr Mendel Tuchman I began to work on urea cycle disorders focus on nitrogen balance and the sensing mechanism of the nitrogen load.

Additional Education

University of Minnesota, St. Paul, MN Post-doc 1998-2000 Biochemistry and Biophysics
Children’s National Medical Center, Washington D.C. Post-doc 2000-2004 Molecular Biology and Biochemistry

Bibliography

  • Djurdjic V, Mandic L, Caldovic L (1989) Determination of non-enzymatic glycosylation levels in plasma proteins. Glasnik hemicara itehnologa Makedonije 7:237-40 (published in Serbo-Croatian)
     
  • Djurdjic V, Mandic L, Caldovic L (1991) Metabolic aspects of trace elements in gallstones. Trace 89:345-9
     
  • Moav B, Liu Z, Caldovic L, Gross ML, Farras AJ, Hackett PB (1993) Regulation of expression of transgenes in developing fish. Transgen Res 2:153-61
     
  • Caldovic L, Hackett PB (1995) Development of position-independent expression vectors and their transfer into transgenic fish. Mol Marine Biol Biotech 4:51-61
     
  • Caldovic L, Agalliu D, Hakett PB (1999) Position-independent expression of transgenes in zebrafish. Transgen Res 8:321-34
     
  • Caldovic L, Morizono H, Gracia Panglao M, Gallegos R, Yu X, Shi D, Malamy MH, Allewell NM, Tuchman M (2002) Cloning and expression of the human N-acetylglutamate synthase gene. Biochem Biophys Res Commun 299(4):581-6
     
  • Caldovic L, Morizono H, Yu X, Thompson M, Shi D, Gallegos R, Allewell NM, Malamy MH,Tuchman M (2002) Identification, cloning and expression of the mouse N-acetylglutamate gene. Biochem J 354:825-31
     
  • Caldovic L, Tuchman M (2003) N-acetylglutamate and its changing role through evolution. Biochem J 372: 279-90 (review)
     
  • Caldovic L, Morizono H, Panglao MG, Cheng SF, Packman S, Tuchman M (2003) Null mutations in the N-acetylglutamate synthase gene associated with acute neonatal disease and hyperammonemia. Hum Genet 112(4):364-8
     
  • Caldovic L, Morizono H, Daikhin Y, Nissim I, McCarter RJ, Yudkoff M, Tuchman M (2004) Restoration of ureagenesis in N-acetylglutamate synthase deficiency by N-carbamylglutamate. J Pediatr 145(4):552-4
     
  • Morizono H, Caldovic L, Shi D, Tuchman M (2004) Mammalian N-acetylglutamate synthase.Mol Genet Metab 81(Suppl):4-11
     
  • Shi D, Morizono H, Yu X, Roth L, Caldovic L, Allewell NM, Malamy MH, Tuchman M (2005) Crystal Structure of N-acetylornithine transcarbamylase from Xanthomonas campestris: A novel enzyme in a new arginine biosynthetic pathway found in several eubacteria. J Biol Chem 280(15):14366-9
     
  • Caldovic L, Morizono H, Panglao MG, Lopez GY, Shi D, Summar ML, Tuchman M (2005) Late onset N-acetylglutamate synthase deficiency caused by hypomorphic alleles. Hum Mutat 25(3):293-8
     
  • Caldovic L, Lopez GY, Haskins N, Panglao M, Shi D, Morizono H, Tuchman M (2006) Biochemical Properties of Recombinant Human and Mouse N-acetylglutamate Synthase. Mol Genet Metabol 87(3):226-32
     
  • Shi D, Caldovic L, Jin Z, Yu X, Qu Q, Roth L, Morizono H, Hathout Y, Allewell NM, Tuchman M (2006) Expression, crystallization and preliminary crystallographic studies of a novel bifunctional N acetylglutamate synthase/kinase from Xanthomonas campestris homologous to vertebrate N-acetylglutamate synthase. Acta Crystallograph Sect F Struct Biol Cryst Commun F62:1218-22
     
  • Caldovic L, Morizono H, Tuchman M (2007) Mutations and polymorphisms in the human N-acetylglutamate synthase gene. Human Mutat 27:626-32
     
  • Qu Q, Morizono H, Shi D, Tuchman M, Caldovic L (2007) A novel bifunctional N-acetylglutamate synthase-kinase from Xanthomonas campestris that is closely related to mammalian N-acetylglutamate synthase. BMC Biochem 8:4
     
  • Dobrowolski SF, Ellingson C, Caldovic L, Tuchman M (2007) Streamlined assessment of gene variants by high resolution melt profiling utilizing the ornithine transcarbamylase gene as a model system. Hum Mutat (in press)
     
  • Shi D, Sagar V, Jin Z, Yu X, Caldovic L, Morizono H, Allewell NM, Tuchman M. (2008) The crystal structure of N-acetyl-L-glutamate synthase from Neisseria gonorrhoeae provides insights into mechanisms of catalysis and regulation. Journal of Biological Chemistry, 283(11):7176-84.
     
  • Tuchman M, Caldovic L, Daikhin Y, Horyn O, Nissim I, Nissim I, Korson M, Burton B, Yudkoff M. (2008) N-carbamylglutamate markedly enhances ureagenesis in N-acetylglutamate deficiency and propionic acidemia as measured by isotopic incorporation and blood biomarkers. Pediatric Research, 64(2):213-7
     
  • Haskins N, Panglao M, Qu Q, Majumdar M, Cabrera-Luque J, Morizono H, Tuchman M, Caldovic L. (2008) Inversion of allosteric effect of arginine on N-acetylglutamate synthase, a molecular marker for evolution of tetrapods. BMC Biochemistry, 9: 24
     
  • Min L, Jin Z, Caldovic L, Morizono H, Allewell NM, Tuchman M, Shi D. (2009) Mechanism of allosteric inhibition of N-acetyl-L-glutamate synthase by L-arginine. J Biol Chem. 284: 4873-80

Research

I am interested in mechanisms that the body uses to sense its environment and regulate its metabolism. I have been studying regulation of the urea cycle, a metabolic pathway responsible for disposal of neurotoxic ammonia from the body and trying to understand how the body senses changes in the ammonia load and adjusts levels of urea cycle enzymes and urea production. I have been using several approaches to address this problem: examination of proteins that interact with the urea cycle enzymes and have potential to regulate their levels or activity, transcriptional and proteomic profiling to examine global changes that accompany changes in ammonia load, and study of the function of the cycle throughout evolution.

Link to pubmed publications: http://www.ncbi.nlm.nih.gov/pubmed/?term=caldovic+l

Industry Relationships and Collaborations

This faculty member (or a member of their immediate family) has reported a financial interest with the health care related companies listed below. These relations have been reported to the University and, when appropriate, management plans are in place to address potential conflicts.

  • None