Professor and Director
Department of Biophysics and Biophysical Chemistry
School of Medicine

Ph.D. 1968, Universidad de Buenos Aires, Argentina

mamzel@jhmi.edu

615 WBSB
725 N. Wolfe Street
Baltimore, MD 21205

Office: 410-955-3955
Lab: 410-955-8715

Structural Enzymology–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 pyrophosphates and 2) redox enzymes. These systems include: ATP-synthase, pyrophosphate hydrolases, farnesyl pyrophosphate synthases, phosphoinoside-3-kinases, flavoenzymes, copper hydroxylases, and non-heme iron diooxygenases. All experiments necessary to address mechanistic questions are carried out in the laboratory. Cloning and expression, ultrapurification, kinetic characterization, mutational analysis, mass spectrometry, crystallization, structure determination by x-ray diffraction, and quantum mechanical calculations 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–Binding and recognition are basic aspects of most biological processes.  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 (DeltaG, DeltaH, DeltaS) that take place when a protein recognizes 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.

Selected Publications
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, C.H., D. Mandelker, S.B. Gabelli, and L.M. Amzel. (2008) Insights into the oncogenic effects of PIK3A mutations from the structure of p110alpha /p85d. Cell Cycle 7:1151-1156.

Huang, C.H., D. Mandelker, O. Schmidt-Kittler, Y. Samuels, V.E. Velculescu, K.W. Kinzler, B. Vogelstein, S.B. Gabelli, and L.M. Amzel. (2007) The structure of a human p110alpha/p85alpha complex elucidates the effects of oncogenic PI3Kalpha mutations. Science 318:1744-1748.

Lafont, V., A.A. Armstrong, H. Ohtaka, Y. Kiso, L.M. Amzel, and E. Freire. (2007) Compensating enthalpic and entropic changes hinder binding affinity optimization. Chem. Biol. Drug Des. 69:413-422. (C)

Pabon, G., and L.M. Amzel. (2006) Mechanism of titin unfolding by force: Insight from Quasi-equilibrium molecular dynamics calculations. Biophys. J. 91:467-472.

Gabelli, S.B., J.S. McLellan, A. Montalvetti, E. Oldfield, R. Docampo, and L.M. Amzel. (2006) Structure and mechanism of the farnesyl pyrophosphate synthase from Trypanosoma cruzi: implications for drug design. Proteins 62:80-88.

Nadella, M., M.A. Bianchet, S.B. Gabelli, J. Barrila, and L.M. Amzel. (2005) Structure and activity of the axon guidance protein MICAL. Proc. Natl. Acad. S 102:16830-16835.