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Publication-Lamango

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PRINCIPAL INVESTIGATOR Nazarius Lamango, Ph.D. College of Pharmacy and Pharmaceutical Sciences 1515 South Martin Luther King Jr. Blvd., Frederick S. Humphries Science Research Center, Suite 209-G Florida A&M University Tallahassee, FL 32307 Telephone: 850-412-7377 E-mail: [email protected]: Significance of Esterases in Prenylation Biochemistry - (Regular Score Project) Prenylation and subsequent S-adenosyl-L-methionine (SAM)-dependent methylation are essential secondary modifications for the biological activity of a significant proportion of eucaryotic proteins. Proteins such as the G-protein γ-subunits of G-protein coupled receptors, nuclear lamins, some receptors and enzymes and monomeric guanine nucleotide binding proteins such as the Ras and Rab related proteins are prenylated and undergo SAM-dependent methylation by prenylated protein methyl transferase (PPMTase). Prenylated methylated protein methyl esterase (PMPMEase) readily hydrolyses the methyl esters forming the unmethylated proteins and methanol. The importance of the prenylation on protein-protein interactions has been demonstrated by the presence of an isoprenyl binding pocket on Rho dissociation inhihibitor. Also, knockout mice lacking PPMTase activity did not survive through mid gestation. The implications of aberrant prenylated protein metabolism on health are therefore enormous. The significance of PMPMEase in the pathway remains to be determined. We have synthesized a specific UV-detectable high affinity small molecule substrate (Benzoyl-Glycyl-FarnesyICysteine Methyl ester, BzGFCM) for the assay of PMPMEase. PMPMEase hydrolyses BzGFCM in a time- and concentration-dependent manner. PMPMEase is inhibited by submicromolar concentrations of organophosphorus pesticides (OPs) and phenylmethylsulfonylfluoride (PMSF) which are mechanism-based inactivators of various serine hydrolases. PMPMEase has neither been properly characterized nor purified thus making its physiological and possible clinical relevance even less understood. The specific aims are to (1) PMPMEase will thus be purified from porcine liver using a sequence of chromatographic techniques (2) The purified PMPMEase will be characterized with synthetic PC analog substrates and recombinant prenylated protein substrates, and (3) A strategy that exploits the high affinity/targeting role of the isoprenyl moiety (that characterizes BzGFCM as well as endogenous prenylated proteins) with the irreversible inhibitory component of PMSF/OPs to synthesize more potent and specific mechanism-based inactivator of PMPMEase. These objectives are to establish the physiological role of PMPMEase, possible involvement in disease and validate its potential as a chemotherapeutic target. PATENTS N.S. Lamango & C.G. Charlton. Method for treatment of a neurological disease characterized by impaired neurological function. U.S. patent number 6,372,793. Issued in 2002. PUBLISHED PUBLICATIONS - 1991-2005 Lamango, N.S. Liver Prenylated Methylated Protein Methyl Esterase is an Organophosphate-Sensitive Enzyme. J. Biochem. Mol. Tax., 19 347-357,2005.Lee, E, H Chen, K R Shephard, N Lamango, K F A Soliman and CG Charlton. Inhibitory Effects of Iysophosphatidylcholine on the dopaminergic system. Neurochemical Research 29: 1325-1334 (2004 ) Lee, E, H Chen, K R Shephard, N Lamango, K F A Soliman and CG Charlton. The inhibitory role of methylation on the binding characteristics of dopamine receptors and transporter. Neuroscience Research 48: 335-344 (2004). Nazarius S. Lamango, Lambert T. Ayuk-Takem, Robert Nesby, Wan-Qian Zhao and Clivel G. Charlton (2003) Inhibition Mechanism of S-Adenosylmethionine-induced Movement Deficits by Prenylcysteine Analogs. Pharmacol. Biochem. Behav. 76: 433-442. Zhao WQ, Williams Z, Shepherd KR, Reuben JS, Lee ES, Darling-Reed S, Lamango N, Soliman KF, Charlton CG. (2002) S-adenosyl-methionine-induced apoptosis in PC12 cells. J Neurosci Res. 69: 519-529. N.S. Lamango & C.G. Charlton (2000) Farnesylcysteine analogs block the S-adenosyl-Lmethionine-induced Parkinson's disease-like symptoms in rats. Pharmacol. Biochem. Behav. 66: 841-849. Zhao, W.Q., Latinwo, L., Liu, X.X, Lee, E.S., Lamango, N.S., Charlton, C.G. (2001) L-DOPA upregulates the expression and activities of methionine adenosyl transferase and catechol-O-methyltransferase. Experimental Neurology. Exp. Neurol. 171: 127-138. N.S. Lamango, R.A. Nesby & C.G. Charlton (2000) Quantitative Determination of SAdenosyl-L-Methionine-Induced Parkinson's Disease-like Tremors in Rats. Pharmacol. Biochem. Behav. 65: 523-529. N.S. Lamango, E. Apletalina, J. Liu. and I. Lindberg (1999) The proteolytic maturation of prohormone convertase 2 (PC2) is a pH-driven process. Arch. Biochem. Biophys. 362: 275-282. E. Apletalina, J. Appel, Lamango, N.S., R.A. Houghten & I. Lindberg (1998) Identification of inhibitors of prohormone convertases 1 and 2 using a peptide combinatorial library. J. BioI. Chem. 273: 26589-26595. K. Johanning, M.A Juliano, L. Juliano, C. Lazure, Lamango, N.S., D.F. Steiner & I. Lindberg (1998) Specificity of prohormone convertase 2 on proenkephalin and proenkephalin-related substrates. J. BioI. Chem. 273: 22672-22680. N.S. Lamango, RJ. Nachman, I.K. Hayes, A. Strey & R.E. Isaac (1997) Hydrolysis of insect neuropeptides by an angiotensin converting enzyme from the housefly, M. domestica. Peptides 18: 47-52. Isaac, RE., Lamango, N.S., Nachman, R.J., Strey, A. & Hayes, T.K. (1997) Angiotensinconverting enzyme and the metabolism of regulatory peptides in insects. Ann. NY Acad. Sci. 814: 339-341. N.S. Lamango, X. Zhu & I. Lindberg (1996) Purification and enzymatic characterization of recombinant prohormone convertase 2: Stimulation of activity by 21 kDa 7B2. Arch. Biochem. Biophys. 330: 238-250.Zhu, X., Lamango, N.S. & Lindberg, I. (1996) Involvement of a polyproline helix-like structure in the interaction of 7B2 with prohormone convertase 2. J. BioI. Chem. 271: 23582-23589. N.S. Lamango, M. Sajid & R.E. Isaac (1996) The endopeptidase activity and the activation by CI-of angiotensin-converting enzyme is evolutionarily conserved: Purification and properties of an angiotensin converting enzyme from the housefly, Musca domestica. Biochem. J. 314: 639-646. Zhu, X., Rouilles Y., Lamango, N.S., Steiner, D.F. & Lindberg, I. (1995) Internal cleavage of the inhibitory 7B2 CT peptide by PC2: a potential mechanism for its inactivation. Proc. Natl. Acad. Sci. USA 93: 4919-4924.


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