Whitman, Christian

Christian P Whitman

Professor
College of Pharmacy

Romeo T. Bachand, Jr. Regents Professor in Pharmacy


whitman@austin.utexas.edu

Phone: 512-471-6198

Office Location
BME 6.202A

Postal Address
The University of Texas at Austin
College of Pharmacy
1 University Station A1900
Austin, TX 78712

Our research focuses on mechanistic, kinetic, and structural studies of the enzymes involved in the bacterial degradation of aromatic and halogenated compounds. One goal is to better understand the relationship between structure and function in enzyme-catalyzed reactions and to provide a molecular description of the factors that govern protein structure, substrate recognition, and reaction specificity. A second goal is to obtain insight into how enzymes and new activities evolve with implications for the development of microbial drug resistance. We discovered the tautomerase superfamily, a group of enzymes defined by a β−α−β structural motif and a catalytic amino-terminal proline, and characterized several members. All previous characterized members are found in catabolic pathways, but a recently discovered member (designated TomN) is in a biosynthetic pathway for one ring of the anti-tumor agent, tomaymycin. Tomaymycin is one of the pyrrolo[1,4]benzodiazepine (PDB) natural products that include anthramycin and sibiromycin. The C ring of tomaymycin is generated in five enzyme-catalyzed steps from L-tyrosine. Functions for the corresponding enzymes have been tentatively assigned, but there is limited biochemical evidence supporting the assignments. The results provide a model for how the ring is made in the PDBs. Another project expands our work on microbial degradation to the pathways used for the catabolism of polycyclic aromatic hydrocarbons (PAHs). These pathways are complex and the enzymes are incompletely characterized, particularly the ones used to process the high molecular weight PAHs. This aim takes advantage of the properties of acetylene compounds. We have a long history of synthesizing and using such compounds as mechanistic probes and inhibitors of hydratases and other enzymes. Our work combines synthesis, mechanistic enzymology, enzyme purification and characterization, molecular biology, spectroscopy, and crystallography to determine the mechanism and structure of enzymes, and to elucidate pathways.

Kinetic, mutational, and structural analysis of malonate semialdehyde decarboxylase from Coryneform bacterium strain FG41: mechanistic implications for the decarboxylase and hydratase activities (2013) Biochemistry 52, 4830-4831.

 

A mutational analysis of the active site loop residues in cis-3-chloroacrylic acid dehalogenase (2013) Biochemistry 52, 4204-4216.

 

A pre-steady-state kinetic analysis of the αY60W mutant of trans-3-chloroacrylic acid dehalogenase: implications for the mechanism of the wild type enzyme (2012) Biochemistry 51, 9420-9435.

 

Reaction of cis-3-chloroacrylic acid dehalogenase with an allene substrate, 2,3-butadienoate: hydration via an enamine, (2012) J. Am. Chem. Soc. 134, 293-304.

 

Kinetic, crystallographic, and mechanistic characterization of TomN: elucidation of a function for a 4-oxalocrotonate tautomerase homologue in the tomaymycin biosynthetic pathway (2011) Biochemistry 35, 7600-7611.

 

Crystal Structures of Native and Inactivated cis-3-Chloroacrylic Acid Dehalogenase: Implications for the Catalytic and Inactivation Mechanisms (2011) Bioorg Chem 39, 1-9.

 

Kinetic and structural characterization of DmpI from Helicobacter pylori and Archaeoglobus fulgidus, two 4-oxalocrotonate tautomerase family members (2010) Bioorg Chem 38, 252-259.

 

Kinetic and structural characterization of a heterohexamer 4-oxalocrotonate tautomerase from Chloroflexus aurantiacus J-10-fl: implications for functional and structural diversity in the tautomerase superfamily (2010) Biochemistry 49, 5016-5027 .

 

Structure of the Proline Utilization A Proline Dehydrogenase Domain Inactivated by N-Propargylglycine Provides Insight into Conformational Changes Induced by Substrate Binding and Flavin Reduction (2010) Biochemistry 49, 560-569 .

 

Pre-Steady State Kinetic Analysis of cis-3-Chloroacrylic Acid Dehalogenase: Analysis and Implications (2009) Biochemistry 48, 11737-11744

 

Reaction Mechanism of cis-3-Chloroacrylic Acid Dehalogenase - A Theoretical Study (2009) Biochemistry 48, 9641-9649 .

 

Structural and Mechanistic Analysis of trans-3-Chloroacrylic Acid Dehalogenase Activity (2008) Acta Crystallogr. D Biol. Crystallogr. 64, 1277-1282 .

 

The Chemical Versatility of the β−α−β Fold: Catalytic Promiscuity and Divergent Evolution in the Tautomerase Superfamily (2008) Cell. Mol. Life Sci. 65, 3606-3618 .

 

Inactivation of Cg10062, a cis-3-Chloroacrylic Acid Dehalogenase Homologue in Corynebacterium glutamicum, by (R)- and (S)-Oxirane-2-carboxylate: Analysis and Implications (2008) Biochemistry 47, 8796-8803 .

 

Characterization of Cg10062 from Corynebacterium glutamicum: Implications for the Evolution of cis-3-Chloroacrylic Acid Dehalogenase Activity in the Tautomerase Superfamily (2008) Biochemistry 47, 8139-8147 .

 

Structural Basis for the Inactivation of Thermus thermophilus Proline Dehydrogenase by N-Propargylglycine (2008) Biochemistry 47, 5573-5580 .

 

Kinetic and Stereochemical Analysis of YwhB, a 4-Oxalocrotonate Tautomerase Homologue in Bacillus subtilis: Mechanistic Implications for the YwhB- and 4-Oxalocrotonate Tautomerase-catalyzed Reactions (2007) Biochemistry 46, 11919-11929 .

 

Graduate Students:

  • Serrano, Hector

Post Doc Students:

  • Almrud, Jeffrey J.
  • Bembenek, Michael
  • Burks, Elizabeth
  • Czerwinski, Robert
  • Hajipour, G.
  • Johnson, William H.
  • Poelarends, Gerrit