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L. Mario Amzel
Professor and Director
Johns Hopkins University School of Medicine
725 N. Wolfe St., 606 WBSB
Baltimore, MD    21205

Fax: 410-955-0637  
Lab: 410-955-8715  
Email: mamzel@jhmi.edu
Assistant: Tammy Watson
Departmental Contact:
Teresa Pennington
Lab Website: http://biophysics.med.jhmi.edu/amzelm/
  Research Interests: Structural enzymology of redox and phosphoryl-transfer enzymes: MICAL, VP14, PI3K, and Nudix hydrolases. Selected areas of structural thermodynamics.

Structural Mechanistic Biochemistry. Enzymes play a key role in all metabolic and cell-signaling processes. Characterization of an enzyme’s biological function must include the description of its mechanisms at an atomic level. Our laboratory is deciphering the catalytic mechanism of several enzyme families, using a combination of molecular biology, biochemistry and structural Biology. Systems under study fall into two classes: 1) Enzymes that recognize or process phosphates and 2) redox enzymes. These systems include: ATP-synthase, pyrophosphate hydrolases, farnesyl pyrophosphate synthases, PI3K, flavoenzymes, copper hydroxylases, and non-heme iron oxygenases. All experiments necessary to address mechanistic questions are carried out in the laboratory. Cloning and expression, ultrapurification, kinetic characterization, mutational analysis, mass spectrometry, crystallization, and structure determination by x-ray diffraction are some of the techniques we bring to bear to characterize the mechanisms of these enzymes. In addition to being intrinsically interesting some of these systems are being developed as targets for drug design.
Structural Thermodynamics.
Most biological processes rely upon recognition and binding among macromolecules. We have developed several systems, such as anti-peptide antibodies and lectins, that we are using to study protein-ligand interactions. As part of this research, we are developing computational methods to calculate the changes in the thermodynamic variables (ΔG, ΔH, ΔS) that take place when a protein recognized another macromolecule or a small ligand. Techniques used in this work involve monoclonal antibody development, x-ray diffraction and calorimetry, followed by empirical parameterization, and molecular mechanics/dynamics and statistical mechanics calculations. Results of these studies have a major impact on our understanding of binding energetics, including the estimation of binding affinities for structure-based drug design.
  Relevant Publications:  

Echeverria, I and Amzel, LM. (2011) Disaccharide Binding to Galectin-1: Free Energy Calculations and Molecular Recognition Mechanism, Biophys J  100(9)2283-92.

Boto A, Xu WL, Jakovcic J, Pannuri A, Romeo T, Bessman MJ, Gabelli SB,  and Amzel LM.  (2011) Structure studies of the Nudix GDP-mannose hydrolase from E. Coli reveals a new motif for mannose recognition.  Proteins  79(8):2455-66.

Duong-Ly K, Gabelli, SB, Xu WL, Dunn CA, Bessman MJ, and Amzel LM. (2011)  The Nudix hydrolase CDP-Chase, a CDP-choline pyrophosphatase, is an asymmetric dimer with two distinct enzymatic activities.  J. Bacteriol. 193(13):3175-85.

Gabelli SB, Mandelker D, Schmidt-Kittler O, Vogelstein B, Amzel LM. (2010) Somatic mutations in PI3Kalpha: Structural basis for enzyme activation and drug design. Biochim Biophys Acta. 1804(3):533-540.

Echeverria I, Amzel LM. (2010) Helix propensities calculations for amino acids in alanine based peptides using Jarzynski's equality.  Proteins. 78(5):1302-10.

Barrila J, Gabelli S, Bacha, U, Amzel L, and Freire E. (2010) Mutation of Asn29 disrupts the dimerization and enzymatic activity of SARS 3CLpro.  Biochemistry 49(20):4308-17.

Huang C-H, Gabelli, SB, Oldfield E, and Amzel LM. (2009) Binding of nitrogen-containing bisphosphonates (N-BPs) to the Trypanosoma cruzi farnesyl diphosphate synthase homodimer.  Proteins: Structure & Bioinformatics 78(4): 888-99 PubMed Abstract

Chufan, E.E., M. De, B.A. Eipper, R.E. Mains, and L.M. Amzel. (2009) Amidation of bioactive peptides: the structure of the lyase domain of the amidating enzyme. Structure 17:965-973.

Huang CH, Mandelker D, Gabelli SB, Amzel LM. (2008) Insights into the oncogenic effects of /PIK3CA/ mutations from the structure of p110alpha/p85alpha. Cell Cycle Feb 27; 7(9).
PubMed Abstract

Bianchet MA, Erdemli SB, and Amzel LM  (2008) Structure, function and mechanism of cytosolic quinone reductases.  Vitamins & Hormones  vol 78:63-84 (Review).
PubMed Abstract

Huang CH, Mandelker D, Schmidt-Kittler O, Samuels Y, Velculescu VE, Kinzler KW, Vogelstein B, Gabelli SB, Amzel LM. (2007) The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318(5857):1744-8.
PubMed Abstract

Gabelli SB, Bianchet MA, Xu WL, Dunn CA, Niu Z-D, Amzel L, and Bessman MJ. (2007) Structure and function of the E.coli dihydroneopterin triphosphates pyrophosphatase: A Nudix enzyme involved in folate biosynthesis.  Structure 15:1014-1022 (C).
PubMed Abstract  

Bianchet MA and Amzel LM (2007) Making the right moves.  Structure 15(8): 885-6.
PubMed Abstract

Parker JB, Bianchet MA, Krosky DJ, Friedman JI, Amzel LM and Stivers JT.  (2007) Enzymatic capture of an extrahelical thymine in the search for uracil in DNA.  Nature 449(7161):433-7.
PubMed Abstract

(C) - cover illustration

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