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Charles T. Grubmeyer, PhDCharles T. Grubmeyer , PhD

 

Professor, Biochemistry

Professor, Fels Institute for Cancer Research

and Molecular Biology
Telephone:  215-707-4495

Fax:  215-707-2805

Email: ctg@temple.edu

 

Department of Biochemistry

Fels Institute for Cancer Research and Molecular Biology

 

Educational Background:

 

University of Alberta, Canada

 

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Research Interests:

 

The laboratory of Charles Grubmeyer studies the structure and function of the enzyme of nucleotide synthesis, particularly the phosphoribosyltransferases (PRTases). The PRTases make nucleoside monophosphates from the cognate nucleobase and the ribose 5-phosphate donor PRPP. Hypoxanthine-guanine PRTases from humans, Tritrichomonas, Plasmodium falciparum and Bacilli are all under active study, together with bacterial quinolinate, nicotinate and orotate PRTases.


X-ray structures solved with collaborating labs show that PRTases exist in open and closed forms. The open forms are compatible with substrate binding and product release, but are not catalytically competent. The closed forms carry out rapid chemical catalysis but then need to open to release products. The linkage between protein movement and enzyme chemistry is a vital topic in contemporary enzymology, and orotate PRTase provides an excellent model system. With collaborator Mark Girvin of Albert Einstein College of Medicine, we use NMR approaches to study the linkage of movement and chemical catalysis. The NMR allows us to follow protein movement, movement of ligands, and their association and dissociation.


The Grubmeyer laboratory utilizes presteady state kinetics to follow events in catalysis. We have Update and Kintek instruments to permit both stopped flow and chemical quench technologies to be employed. When coupled with NMR measurements, the result is a kinetic picture containing both movement and chemical events. We manipulate the system using mutagenesis to disrupt the roles of vital amino acid residues, and alter the movement/chemistry linkage. What is emerging is an apparently tight linkage between movement and chemistry in orotate PRTase, whose disruption allows for generation of dead-end paths for protein movement.

 

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PUBMED PUBLICATIONS :


Recent Medically Related Publications, Obtained from PubMed (Click on PubMed ID to view abstract)

24262852. Hansen MR, Barr EW, Jensen KF, Willemoës M, Grubmeyer C, Winther JR, Catalytic site interactions in yeast OMP synthase. Arch Biochem Biophys 542:(28-38)2014 Jan 15

23315339. Hansen MR, Harris R, Barr EW, Cheng H, Girvin ME, Grubmeyer C, Backbone ¹H, ¹³C, ¹5N NMR assignments of yeast OMP synthase in unliganded form and in complex with orotidine 5'-monophosphate. Biomol NMR Assign 8:1(103-8)2014 Apr

22531099. Wang GP, Hansen MR, Grubmeyer C, Loop residues and catalysis in OMP synthase. Biochemistry 51:22(4406-15)2012 Jun 5

22531064. Grubmeyer C, Hansen MR, Fedorov AA, Almo SC, Structure of Salmonella typhimurium OMP synthase in a complete substrate complex. Biochemistry 51:22(4397-405)2012 Jun 5

20047307. Bello Z, Stitt B, Grubmeyer C, Interactions at the 2 and 5 positions of 5-phosphoribosyl pyrophosphate are essential in Salmonella typhimurium quinolinate phosphoribosyltransferase. Biochemistry 49:7(1377-87)2010 Feb 23

20047306. Bello Z, Grubmeyer C, Roles for cationic residues at the quinolinic acid binding site of quinolinate phosphoribosyltransferase. Biochemistry 49:7(1388-95)2010 Feb 23

11876660. Cao H, Pietrak BL, Grubmeyer C, Quinolinate phosphoribosyltransferase: kinetic mechanism for a type II PRTase. Biochemistry 41:10(3520-8)2002 Mar 12

10506999. Grubmeyer CT, Gross JW, Rajavel M, Energy coupling through molecular discrimination: nicotinate phosphoribosyltransferase. Methods Enzymol 308:(28-48)1999

10353848. Teng H, Grubmeyer C, Mutagenesis of histidinol dehydrogenase reveals roles for conserved histidine residues. Biochemistry 38:22(7363-71)1999 Jun 1

10353847. Grubmeyer C, Teng H, Mechanism of Salmonella typhimurium histidinol dehydrogenase: kinetic isotope effects and pH profiles. Biochemistry 38:22(7355-62)1999 Jun 1

9890909. Wang GP, Cahill SM, Liu X, Girvin ME, Grubmeyer C, Motional dynamics of the catalytic loop in OMP synthase. Biochemistry 38:1(284-95)1999 Jan 5

9890908. Wang GP, Lundegaard C, Jensen KF, Grubmeyer C, Kinetic mechanism of OMP synthase: a slow physical step following group transfer limits catalytic rate. Biochemistry 38:1(275-83)1999 Jan 5

9521741. Gross JW, Rajavel M, Grubmeyer C, Kinetic mechanism of nicotinic acid phosphoribosyltransferase: implications for energy coupling. Biochemistry 37:12(4189-99)1998 Mar 24

9521740. Rajavel M, Lalo D, Gross JW, Grubmeyer C, Conversion of a cosubstrate to an inhibitor: phosphorylation mutants of nicotinic acid phosphoribosyltransferase. Biochemistry 37:12(4181-8)1998 Mar 24

9521733. Xu Y, Grubmeyer C, Catalysis in human hypoxanthine-guanine phosphoribosyltransferase: Asp 137 acts as a general acid/base. Biochemistry 37:12(4114-24)1998 Mar 24

9132023. Xu Y, Eads J, Sacchettini JC, Grubmeyer C, Kinetic mechanism of human hypoxanthine-guanine phosphoribosyltransferase: rapid phosphoribosyl transfer chemistry. Biochemistry 36:12(3700-12)1997 Mar 25

9003389. Garriga J, Segura E, Mayol X, Grubmeyer C, Graña X, Phosphorylation site specificity of the CDC2-related kinase PITALRE. Biochem J 320 ( Pt 3):(983-9)1996 Dec 15

8672422. Gross J, Rajavel M, Segura E, Grubmeyer C, Energy coupling in Salmonella typhimurium nicotinic acid phosphoribosyltransferase: identification of His-219 as site of phosphorylation. Biochemistry 35:13(3917-24)1996 Apr 2

8672421. Rajavel M, Gross J, Segura E, Moore WT, Grubmeyer C, Limited proteolysis of Salmonella typhimurium nicotinic acid phosphoribosyltransferase reveals ATP-linked conformational change. Biochemistry 35:13(3909-16)1996 Apr 2

7545006. Ozturk DH, Dorfman RH, Scapin G, Sacchettini JC, Grubmeyer C, Structure and function of Salmonella typhimurium orotate phosphoribosyltransferase: protein complementation reveals shared active sites. Biochemistry 34:34(10764-70)1995 Aug 29

7545005. Ozturk DH, Dorfman RH, Scapin G, Sacchettini JC, Grubmeyer C, Locations and functional roles of conserved lysine residues in Salmonella typhimurium orotate phosphoribosyltransferase. Biochemistry 34:34(10755-63)1995 Aug 29

8376388. Grubmeyer C, Segura E, Dorfman R, Active site lysines in orotate phosphoribosyltransferase. J Biol Chem 268:27(20299-304)1993 Sep 25

8314784. Teng H, Segura E, Grubmeyer C, Conserved cysteine residues of histidinol dehydrogenase are not involved in catalysis. Novel chemistry required for enzymatic aldehyde oxidation. J Biol Chem 268:19(14182-8)1993 Jul 5

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