Faculty Directory

Hiroki Morizono Hiroki Morizono
Associate Research Professor of Genomics and Precision Medicine
Associate Research Professor of Pediatrics (Secondary)

Office Phone: 202-476-6029
Email: Email
Department: Genomics and Precision Medicine

Education

  • B.S., Massachusetts Institute of Technology, 1987
  • PhD, University of Minnesota, Minneapolis-St. Paul, 1997

Biography

My lab is interested in nitrogen metabolism, a central process for converting nutrients and waste products into the building blocks of cells, energy production and metabolic detoxification. We use the vertebrate urea cycle and bacterial arginine biosynthesis pathways as our model systems. Our research seeks to categorize and understand the biological scales and mechanisms by which mutations in urea cycle enzymes cause disease, and to develop therapies to treat disorders of nitrogen metabolism. I have a deep-seated interest in the relationships between sequence, structure, and function of proteins, particularly novel variations of questons including how does an amino acid sequence fold into a particular three dimensional shape? What are the forces that hold the protein in this folded shape? Why does this conformation catalyze a chemical reaction? Which regions of a protein are affected when mutations occur, and how do mutations affect its catalytic activity? Insights into these questions let us predict if an inherited mutation might be deleterious, and are also forms the basis for understanding how the different proteins and enzymes interact in our cells and our bodies.

Additional Education

University of Minnesota Medical School  Post-doc 1997-1999 Pediatrics
Children’s National Medical Center  Post-doc 1999-  Pediatrics/Genetic/Biochemistry

Bibliography

Selected from 40:

  • Wang L, Wang H, Bell P, McCarter RJ, He J, Calcedo R, Vandenberghe LH, Morizono H, Batshaw ML, Wilson JM. Systematic evaluation of AAV vectors for liver directed gene transfer in murine models. Mol Ther. 2010 Jan;18(1):118-25. Epub 2009 Oct 27. PubMed PMID: 19861950.
     
  • Haskins N, Panglao M, Qu Q, Majumdar H, Cabrera-Luque J, Morizono H, Tuchman M, Caldovic L. Inversion of allosteric effect of arginine on N-acetylglutamate synthase, a molecular marker for evolution of tetrapods. BMC Biochem. 2008 Sep 18;9:24. PubMed PMID: 18801197; PubMed Central PMCID: PMC2566978.
     
  • Caldovic L, Morizono H, Tuchman M. Mutations and polymorphisms in the human N-acetylglutamate synthase (NAGS) gene. Hum Mutat. 2007 Aug;28(8):754-9. PubMed PMID: 17421020.
     
  • Yamaguchi S, Brailey LL, Morizono H, Bale AE, Tuchman M. Mutations and polymorphisms in the human ornithine transcarbamylase (OTC) gene. Hum Mutat. 2006 Jul;27(7):626-32. PubMed PMID: 16786505.
     
  • Moscioni D, Morizono H, McCarter RJ, Stern A, Cabrera-Luque J, Hoang A, Sanmiguel J, Wu D, Bell P, Gao GP, Raper SE, Wilson JM, Batshaw ML. Long-term correction of ammonia metabolism and prolonged survival in ornithine transcarbamylase-deficient mice following liver-directed treatment with adeno-associated viral vectors. Mol Ther. 2006 Jul;14(1):25-33. Epub 2006 May 3.  PubMed PMID: 16677864.
     
  • Morizono H, Cabrera-Luque J, Shi D, Gallegos R, Yamaguchi S, Yu X, Allewell NM, Malamy MH, Tuchman M. Acetylornithine transcarbamylase: a novel enzyme in arginine biosynthesis. J Bacteriol. 2006 Apr;188(8):2974-82. PubMed PMID: 16585758; PubMed Central PMCID: PMC1446984.
     
  • Morizono H, Woolston JE, Colombini M, Tuchman M. The use of yeast mitochondria to study the properties of wild-type and mutant human mitochondrial  ornithine transporter. Mol Genet Metab. 2005 Dec;86(4):431-40. Epub 2005 Oct 26.  PubMed PMID: 16256388.
     
  • Morizono H, Caldovic L, Shi D, Tuchman M. Mammalian N-acetylglutamate synthase. Mol Genet Metab. 2004 Apr;81 Suppl 1:S4-11. Review. PubMed PMID: 15050968.
     
  • Morizono H, Listrom CD, Rajagopal BS, Aoyagi M, McCann MT, Allewell NM, Tuchman M. 'Late onset' ornithine transcarbamylase deficiency: function of three  purified recombinant mutant enzymes. Hum Mol Genet. 1997 Jun;6(6):963-8. PubMed PMID: 9175746.
     
  • Morizono H, Tuchman M, Rajagopal BS, McCann MT, Listrom CD, Yuan X, Venugopal D, Barany G, Allewell NM. Expression, purification and kinetic characterization of wild-type human ornithine transcarbamylase and a recurrent mutant that produces 'late onset' hyperammonaemia. Biochem J. 1997 Mar 1;322 ( Pt 2):625-31.  PubMed PMID: 9065786; PubMed Central PMCID: PMC1218235.

Research

Urea cycle and arginine biosynthesis: We use the urea cycle as a model system because it is a central metabolic pathway whose disruption has devastating effects. Systems biology approaches allow us to model the production of urea and relate it to changes in protein stability, protein interactions, gene expression, metabolite transport, cellular dynamics, and organ interactions. We have applied this type of analysis to ornithine transcarbamylase, the mitochondrial ornithine/citrulline transporter, and to N-acetylglutamate synthase. We have recently discovered two novel enzymes that are structurally and functionally related to ornithine transcarbamylase—they appear to have branched from the aspartate transcarbamylase and ornithine transcarbamylase at a point in time very near to the last universal common ancestor to all life on earth—the existence of these enzymes requires changes to the canonical arginine biosynthetic pathway, and provide clues as to the origins of this pathway.

Website: http://ureacycle.cnmcresearch.org

Gene Therapy: For severe defects of the urea cycle, liver transplantation remains the recommended treatment. However, liver transplantation involves major surgery and is limited by donor availability and suitability. We are interested in developing a gene therapy approach to treatment of urea cycle disorders beginning with the most prevalent of the inherited urea cycle disorders, ornithine transcarbamylase deficiency.  In collaboration with the laboratories of James Wilson and Lili Wang at University of Pennsylvania, we have developed a third generation adeno-associated virus vector that is being evaluated for stability and safety as well as rapidity and magnitude of gene expression.

Link to PubMed publications: http://www.ncbi.nlm.nih.gov/pubmed/?term=morizono+h

Publications

View publications by this faculty member.

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