Our laboratory has a long-standing interest in the relationship between macromolecular structure and function, in particular the role of cat ions and anions in modulating protein conformation and enzyme activity. Currently most of our effort is focused in two areas: (1) the factors modulating the ryanodine receptor and (2) the interaction between capsular polysaccharide and two proteins, immunoglobin and complement factor C3.

The ryanodine receptor is an intracellular calcium channel best characterized in muscle cells where it forms a critical element of the excitation-contraction coupling process. Recent studies suggest that the ryanodine receptor may also be responsible for modulating calcium ion levels in other cell types.

Virulence of many pathogens is associated with the production of a polysaccharide capsule surrounding the organism. We are investigating the nature of the protein-polysaccharide interaction to understand the disease process itself as well as to gain new insights into carbohydrate-mediated events in intra- and intercellular communication.

We use a variety of physical techniques in our research including analytical ultra centrifugation, computational biochemistry, molecular visualization, spectrofluorimetry and other forms of optical spectroscopy, kinetic and thermodynamic analysis.

R. Scavetta, D. Chu, J. Gosar, R. Siedel, J. Hoyt, K. Schegg and W. Welch, "Captan Produces Differential, in Vivo Inhibition of Esterase Activity in Penicillium dupontii and Penicillium chrysogenum."  Pesticide Biochemistry and Physiology. 38:81-91 (1990). 

T.R. Kozel, M.S. Wilson and W.H. Welch, "Kinetic Analysis of the Amplification Phase for Activation and Binding of C3 to Encapsulated and Nonencapsulated Cryptococcus neoformans." Infection and Immunity, 60:3122-3127 (1992). 

P. Gu, W.H. Welch and G.J. Blomquist, "Methyl-Branched Fatty Acid Biosynthesis in the German Cockroach Blattella germanica: Kinetic Studies Comparing a Microsomal and Soluble Fatty Acid Synthetase." Insect Biochem. Molec. Biol. 23:263-271 (1993).

R.C. Reitz, D.J. Mead and W.H. Welch, Jr., "Phospholipid Methylation in Brain Membrane Preparations: Kinetic Mechanism." Biochim. Biophys. Acta, 1166:139-144 (1993). 

E.W. Otteson, W. Welch and T.R. Kozel, "Protein-Polysaccharide Interactions: A Monoclonal Antibody Specific for the Capsular Polysaccharide of Cryptococcus neoformans." J. Biol. Chem. 269:1858-1864 (1994). 

W. Welch, S. Ahmad, J. A. Airey, K. Gerzon, R. Humerickhouse, H. R. Besch, Jr., L. Ruest, P. Deslongchamps and J. L. Sutko, "Structural Determinants of High Affinity Binding of Ryanoids to the Vertebrate Skeletal Muscle Ryanodine Receptor: A Comparative Molecular Field Analysis." Biochemistry.  33:6074-6085 (1994). 

H.-M. P. Wilson, W. Neumuller, H. Elbi, W. H. Welch, Jr. and R. C. Reitz, "The Structural Basis of the Phospholipid Acyltransferase Enzyme Substrate Specificity: A Computer Modeling Study of the Phospholipid Acceptor Molecule." J. Lipid Research. 36:429-439 (1995).

W. Welch, J. L. Sutko, K. E. Mitchell, J. Airey, and L. Ruest. “The Pyrrole Locus Is the Major Orienting Factor in Ryanodine Binding.”  Biochemistry. 35:7165-7173 (1996).

A. Tinker, J. L. Sutko, L. Ruest, P. Deslongchamps, W. Welch, J. A. Airey, K. Gerzon, K.  R. Bidasee, H. R. Besch, Jr., and A. J. Williams, "The Electrophysiological Effects of Ryanodine Derivatives on the Sheep Cardiac Sarcoplasmic Reticulum Calcium-Release Channel."  Biophysical Journal. 70:2110-2119 (1996).

W. Welch, A. J. Williams, A. Tinker, L. Ruest, K. Mitchell, P. Deslongchamps, J. Lamothe, K. Gerzon, H. R. Besch, Jr., J. A. Airey and J. L. Sutko, "Structural components of ryanodine responsible for modulation of sarcoplasmic reticulum calcium channel function." Biochemistry 36:2939-2950 (1997).

J. L. Sutko, J. A. Airey, W. Welch and L. Ruest, “The Pharmacology of Ryanodine and Related Compounds.”  Pharmacology Reviews 49:53-98 (1997).

P. Gu. W. H. Welch, Lin Guo, K. M. Schegg and G. J. Blomquist, “Characterization of a Novel Microsomal Fatty Acid Synthetase (FAS) Compared to a Cytosolic FAS in the Housefly, Musca domestica.” Comparative Biochemsitry and Physiology Biochem. & Molec. Biol.  118B:447- 456 (1997). 

W. Welch, “The Ryanodine Receptor: A Report from the Ryanoids.”  In A. Williams and R. Sitapesan, editors, Ryanodine Receptors. Imperial College Press, London (1998) pp 111-136. 

S. A. Fraser, Marek Michallak, William H. Welch, and Dorothy Hudig, “Calreticulin, a component of the endoplasmic reticulum and of cytotoxic lymphocyte granules, regulates perforin-mediated lysis in the hemolytic model system.” Biochem. & Cell Biol. 76 (1998) 881-887. 

B. Tanna, W. Welch, L. Ruest, J. L. Sutko and A. J. Williams, “Interactions of a reversible ryanoid (21-amino-9-alpha-hydroxy-ryanodine) with single sheep cardiac ryanodine receptor channels.” J. Gen. Physiol. 112:55-69 (1998). 

D. D. McKemy, W. Welch, J. A. Airey, and J. L. Sutko, “Concentrations of caffeine greater than 20 mM increase the indo-1 fluroescence ratio in a Ca²⁺-independent manner.” Cell Calcium. 27(2):117-124 (2000). 

B. Tanna, W. Welch, L. Ruest, J. L. Sutko, and A. J. Williams, “The interaction of a neutral ryanoid with the ryanodine receptor channel provides insights into the mechanisms by which ryanoid binding is modulated by voltage.” J. Gen. Physiol. 116(1):1-9 (2000). 

W.-M. Chan, W. Welch, R. Sitsapesan, “Structural factors that determine the ability of  adenosine and related compounds to activate the cardiac ryanodine receptor.” Br. J. Pharmacol. 130:1618-1626 (2000).

B. Tanna, W. Welch, L. Ruest, J.L. Sutko, and A.J. Williams, "Ryanoid modification of the cardiac muscle ryanodine receptor channel results in relocation of the tetraethylammonium binding site." J. Gen. Physiol. 117:385-94 (2001).

W. Welch, "Quantitative relationships between ryanoids, receptor affinity and channel conductance." Frontiers in Bioscience Aug. 1; 7 : D1727-42 (2002).

B. Tanna, W. Welch, L. Ruest, J.L. Sutko, and A.J. Williams, "Excess noise in modified conductance states following the interaction of ryanoids with cardiac ryanodine receptor channels." FEBS Lett. 516 : 35-39 (2002).

R.A. Maxwell, W.H. Welch and D.A. Schooley, "JH diol kinase: Part I, Purification, Characterization and Substrate Specificity of Juvenile Hormone Selective Diol Kinase from Manduca sexta." J. Biol. Chem. 277: 21874-21881 (2002).

R.A. Maxwell, W.H. Welch, F. M. Horodyski, K.M. Schegg, and D.A. Schooley, "JH diol kinase: Part II, Sequencing, Cloning and Molecular Modeling of Juvenile Hormone Selective Diol Kinase from Manduca sexta." J. Biol. Chem. 277: 21882-21890 (2002).

W. M. Chan, W. Welch, and R. Sitsapesan, “Structural Characteristics That Govern Binding to, and Modulation through, the Cardiac Ryanodine Receptor Nucleotide Binding Site.” Mol. Pharmacol. 63: 174-182 (2003).

S. H. Schwartz, B. C. Tan, D. R. McCarty, W. Welch, J. A. Zeevaart, “ Substrate specificity and kinetics for VP14, a carotenoid cleavage dioxygenase in the ABA biosynthetic pathway.” Biochim. Biophys. Acta. 1619: 9-14 (2003).

B. Tanna, W. Welch, L. Ruest, J. L. Sutko, A. J. Williams, “An Anionic Ryanoid, 10-O-succinoylryanodol, Provides Insights into the Mechanisms Governing the Interaction of Ryanoids and the Subsequent Altered Function of Ryanodine-receptor Channels.” J. Gen. Physiol. 121:551-561 (2003).

R. Wang, L. Zhang, J. Bolstad, N. Diao, C. Brown, L. Ruest, W. Welch, A. J. Williams, and S. R. W. Chen, “Residue Gln4863 within a predicted transmembrane sequence of the Ca2+ release channel (ryanodine receptor) is critical for ryanodine interaction.” J. Biol. Chem. 278:51557-51565 (2003).

D. C. Sheppard, M. R. Yeaman, W. H. Welch, Q. T. Phan, Y. Fu, A. S. Ibrahim, S. G. Filler, M. Zhang, A. J. Waring, J. E. Edwards Jr., “Functional and structural diversity in the Als protein family of Candida albicans.” J. Biol. Chem. 279:30480-304089. (2004).

W. Welch, S. Rheault, D. West, and A. J. Williams, “A model of the putative pore region of the cardiac ryanodine receptor (RyR2).” Biophys. J. in press for 2004.

N. Y. Yount, K. D. Gank, Y. Q. Xiong, A. S. Bayer, T. Pender, W. H. Welch, and M. R. Yeaman, “Platelet Microbicidal Protein-1: Structural Themes of a Multifunctional Antimicrobial Peptide.” Antimicrobial Agents and Chemotherapy in press for 2004.

Stefan E. Boiadjiev, Kimberly Watters, Steven Wolf, Byron N. Lai, William H. Welch, Antony F. McDonagh and David A. Lightner, “pKa and aggregation of bilirubin: titrimetric and ultracentrifugation studies on water-soluble pegylated conjugates of bilirubin and fatty acids..” Biochemistry 43:15617-15632 (2004).

Jyh-Ching Chou, William H. Welch, and Jerry. D. Cohen, “His-404 and His-405 are essential for enzyme catalytic activities of a bacterial indole-3-acetyl-L-aspartic acid hydrolase.” Plant Cell Physiol. 45:1335-1341 (2004).

B. Tanna, W. Welch, L. Ruest, J. Sutko, and A. Williams. “Voltage-sensitive equilibrium between two states within a ryanoid-modified conductance state of the ryanodine receptor channel.” Biophys. J. 88:2585-2596 (2005).

K. M. Ranatunga, T. K. Moreno-King, B. Tanna, R. Wang, S. R. Chen, L. Ruest, W. Welch, A. J. Williams. “The Gln4863Ala Mutation Within a Putative, Pore-Lining Trans-Membrane Helix Of The Cardiac Ryanodine Receptor Channel Alters Both The Kinetics Of Ryanoid
Interaction And The Subsequent Fractional Conductance.” Mol Pharmacol. 68:840-846 (2005).

A. B. Gilg, J. C. Bearfield, C. Tittiger, W. H. Welch, and G. J. Blomquist. “Isolation and functional expression of an animal geranyl diphosphate synthase and its role in bark beetle pheromone biosynthesis.” Proc Natl Acad Sci U S A. 102:9760-9765 (2005).