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Albert Mildvan Portrait

Albert Mildvan
Professor Emeritus of Biological Chemistry
Johns Hopkins University School of Medicine

JHU School of Medicine
725 N. Wolfe St. 511 Hunterian
BALTIMORE, MD21205
Office Phone: 410-955-2038
Lab Phone: 410-955-3557
Fax: 410-955-5759
Email: mildvan@jhmi.edu

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Mechanisms of enzyme action; enzymes of DNA and ATP hydrolysis; isomerases; nuclear magnetic resonance and electron spin resonance.

To understand the structural basis for the high catalytic power of enzymes, we have studied the mechanisms of enzyme-catalyzed reactions of DNA (DNA Topoisomerase I, Staphylococcal nuclease, DNA polymerase) of ATP (Mut T dNTPase and related Nudix hydrolases) and enzyme-catalyzed polarization of carbonyl groups (ketosteroid isomerase 4-oxalocrotonate tautomerase). Multidimensional heteronuclear NMR, electron spin resonance, chemical and genetic modification of enzymes, and kinetic isotope effects are used to elucidate the structures of enzymes, the role of metals, and the conformations, locations, arrangement, and exchange rates of enzyme-bound substrates. The solution structures of enzymes are determined by ultra-high resolution 1D, 2D and 3D NMR methods. We are currently studying the roles of divalent cations in the mechanism of Methionine aminopeptidase, in collaboration with Professor Jun O. Liu, Department of Pharmacology and Molecular Sciences.
Recent Publications
Czerwinski, R. M., Harris, T.K., Massiah, M.A., Mildvan, A.S., and Whitman, C.W. (2001) The structural basis for the perturbed pKa of the catalytic base in 4-oxalocrotonate tautomerase: Kinetic and structural effects of mutations of Phe-50. Biochemistry 40, 1984-1995.
PubMed Abstract

Massiah MA, Viragh C, Reddy PM, Kovach IM, Johnson J, Rosenberry TL, Mildvan AS. (2001) Short, strong hydrogen bonds at the active site of human acetylcholinesterase: proton NMR studies. Biochemistry. 2001 May 15;40(19):5682-90.
PubMed Abstract

Marks GT, Harris TK, Massiah MA, Mildvan AS, Harrison DH. (2001) Mechanistic implications of methylglyoxal synthase complexed with phosphoglycolohydroxamic acid as observed by X-ray crystallography and NMR spectroscopy. Biochemistry. 2001 Jun 12;40(23):6805-18.
PubMed Abstract

Mildvan, A. S., Massiah, M. A., Harris, T. K., Marks, G. T., Harrison, D. H. T., Viragh, C., Reddy, P. M., and Kovach, I. M. (2002) Short, strong hydrogen bonds on enzymes: NMR and mechanistic studies. J. Molecular structure, 165;163-175.
PubMed Abstract

Massiah MA, Viragh C, Reddy PM, Kovach IM, Johnson J, Rosenberry TL, Mildvan AS. (2001) Short, strong hydrogen bonds at the active site of human acetylcholinesterase: proton NMR studies. Biochemistry. 2001 May 15;40(19):5682-90.
PubMed Abstract

Legler, P. M., Lee, H. Caroline, Peisach, J., and Mildvan, A. S. (2002) Kinetic and magnetic resonance studies of the role of metal ions in the mechanism of E. coli GDP-Mannose mannosyl hydrolase, an unusual Nudix enzyme. Biochemistry 41, 4655-4668.
PubMed Abstract

Bolton EC, Mildvan AS, Boeke JD. (2002) Inhibition of reverse transcription in vivo by elevated manganese ion concentration. Mol Cell. 2002 Apr;9(4):879-89.
PubMed Abstract

Legler, P.M., Massiah, M.A., and Mildvan, A.S. (2002) Mutational, kinetic, and NMR studies of the mechanism of E. coli GDP-Mannose mannosyl hydrolase, an unusual Nudix enzyme. Biochemistry 41, 10834-10848.
PubMed Abstract

Saraswat V, Massiah MA, Lopez G, Amzel LM, Mildvan AS. (2002) Interactions of the products, 8-oxo-dGMP, dGMP, and pyrophosphate with the MutT nucleoside triphosphate pyrophosphohydrolase. Biochemistry. Dec 31;41(52):15566-77.
PubMed Abstract

Massiah MA, Saraswat V, Azurmendi HF, Mildvan AS. (2003) Solution structure and NH exchange studies of the MutT pyrophosphohydrolase complexed with Mg(2+) and 8-oxo-dGMP, a tightly bound product. Biochemistry. Sep 2;42(34):10140-54.
PubMed Abstract

Saraswat, V., Azurmendi, H. F., Mildvan, A. S. (2004) Mutational, NMR, and NH exchange studies of the tight and selective binding of 8-oxo-dGMP by the MutT pyrophosphohydrolase. Biochemistry Mar 30;43(12):3404-14.
PubMed Abstract

Azurmendi H.F., Wang,S.F., Massiah,M.A., Poelarends, G.J., Whitman,C.P., Mildvan A.S. (2004). The roles of active site residues in the catalytic mechanism of trans-3-chloroacrylic acid dehalogenase: a kinetic, NMR, and mutational analysis. Biochemistry; 43:4082-4091.
PubMed Abstract

Gabelli SB, Bianchet MA, Azurmendi HF, Xia Z, Sarawat V, Mildvan AS, Amzel LM. (2004) Structure and mechanism of GDP-mannose glycosyl hydrolase, a Nudix enzyme that cleaves at carbon instead of phosphorus. Structure (Camb). Jun;12(6):927-35.
PubMed Abstract

Mildvan AS, Xia Z, Azurmendi HF, Saraswat V, Legler PM, Massiah MA, Gabelli SB, Bianchet MA, Kang LW, Amzel LM. (2005) Structures and mechanisms of Nudix hydrolases. Archives of Biochemistry and Biophysics. 433: 129-143.
PubMed Abstract

Mildvan AS. (2004) Inverse thinking about double mutants of enzymes. Biochemistry. Nov 23;43(46):14517-20.
PubMed Abstract

Azurmendi HF, Miller SG, Whitman CP, Mildvan AS. (2005) Half-of-the-sites binding of reactive intermediates and their analogs to 4-oxalocrotonate tautomerase and induced structural asymmetry of the enzyme. Biochemistry 44, 7725-7737.
PubMed Abstract

Xia Z, Azurmendi HF, Lairson LL, Withers SG, Gabelli SB, Bianchet MA, Amzel LM, Mildvan AS. (2005) Mutational, structural, and kinetic evidencne for a dissociative mechanism in the GDP-mannose mannosyl hydrolase reaction. Biochemistry Jun 28;44(25):8989-97.
PubMed Abstract

Mildvan, A. S., Xia, Z., Azurmendi, H. F., Legler, P. M., Balfour, M. R., Lairson, L. L., Withers, S. G., Gabelli, S. B., Bianchet, M. A., and Amzel, L. M. (2005) Hydrogen bonding in the mechanism of GDP-mannose mannosyl hydrolase. J. Mol. Structure.

Xia, Z., Azurmendi, H. F., and Mildvan, A. S. (2005) Transient state kinetic studies of the MutT-catalyzed nucleoside triphosphate pyrophosphohydrolase reaction. Biochemistry 44(46), 15334-15344.
PubMed Abstract

Gabelli, S.B., Azurmendi, H.F., Bianchet, M.A., Amzel, L.M. and Mildvan, A.S. (2006) X-ray, NMR, and mutational studies of the catalytic cycle of the GDP-mannose mannosyl hydrolase reaction. Biochemistry 45, 11290-11303
PubMed Abstract


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