Dr. Kerry Smith

Associate Professor
Ph.D. Molecular Biology
1993, University of Pennsylvania
School of Medicine

Research Interests
Microbial Biochemistry
Molecular Enzymology
Microbial Pathogenesis

Office: 220 Biosystems Research Complex
Phone: (864) 656-6935
Email: kssmith@clemson.edu

Research Activities

Acetyl-CoA, an essential intermediate at the junction of various anabolic and catabolic pathways, plays a central role in carbon metabolism in all living organisms. The synthesis of acetyl-CoA from acetate and CoA can occur via three different enzymatic pathways: ADP-forming acetyl-CoA synthetase (ADP-ACS), AMP-forming acetyl-CoA synthetase (ACS) and acetate kinase (AK) - phosphotransacetylase (PTA). The presence of three pathways for the interconversion of acetate and acetyl-CoA underscores the importance of this reaction in the physiology and metabolism of all living organisms.

Substrate binding and catalysis of ACS enzyme family.

The goal of our research is to gain a better understanding of biochemistry of the ACS and the short chain acyl-CoA synthetase family of enzymes to which it belongs. ACS is nearly ubiquitous in all three domains of life and is the key enzyme for synthesis of acetyl-CoA from acetate [ATP + acetate + CoA ↔ acetyl-CoA + AMP + PPi]. In addition to its metabolic role, recent reports indicate ACS also plays a critical role in linking metabolism to other physiological processes, such as global gene regulation in eukaryotes and chemotaxis in bacteria. Furthermore, posttranslational regulation of ACS by acetylation and deacetylation has been shown to be conserved from bacteria to mammals. These findings have brought new attention to this enzyme. Our aim is to gain a better understanding of this important family of enzymes by investigating the evolution of the active site of ACS and through studies of the related acyl-adenylate synthetase (AAS) family of enzymes, which has been shown to be a bifunctional enzyme with both acyl-adenylate and acyl-CoA synthetase activities. The enzymatic activity of AAS is determined by its acyl substrate. The structure of AAS has recently been solved by our collaborator Dr. Andrew Gulick (SUNY-Buffalo).

ACK in eukaryotic microbes.

ACK, previously thought to be found strictly in prokaryotes, was first identified in my lab to be present in certain eukaryotic microbes. ACK is present in a number of significant human pathogens including the fungi Cryptococcus neoformans, Aspergillus fumigatus, Histoplasma capsulatum, and Coccidioides spp. as well as a number of bacterial pathogens listed under the NIAID A, B, and C categories of priority pathogens for biodefense potential. In addition, ACK is present in Entamoeba histolytica, a pathogenic protist. E. histolytica, the third leading cause of morbidity and mortality due to parasitic disease in humans, is also listed by the NIAID as a category B priority pathogen with Bioterrorism Potential. Pathogenic fungi and protists are eukaryotes, making it extremely difficult to identify targets for therapeutic agents that would not also be deleterious to the mammalian host. Thus, the presence of ACK in these pathogens and its absence in humans, animals, and plants may provide a novel target for chemotherapeutic agents.

ACK [ATP + acetate ↔ acetyl phosphate + ADP], along with PTA [acetyl phosphate + CoA ↔ acetyl-CoA + Pi], forms one of three pathways for the interconversion of acetyl-CoA and acetate. In the algae Chlamydomonas reinhardtii and oomycete Phytophthora spp., PTA appears to be the partner enzyme for ACK, as is usually the case in bacteria. However, a PTA resembling either of the bacterial PTAs (PTA and PduL) has not been identified in other eukaryotic microbes. We have identified xylulose 5-phosphate/fructose 6-phosphate phosphoketolase (XFP) as a putative partner enzyme for ACK in all fungi that have ACK. XFP, also previously thought to be a strictly bacterial enzyme, catalyzes the formation of acetyl phosphate from either xylulose 5-phosphate or fructose 6-phosphate and inorganic phosphate. In the protist E. histolytica, no partner enzyme for ACK has been identified from bioinformatics analysis of the genome sequence. However, the genome is not yet completed, raising the possibility that PTA or XFP may be present.

Recent Publications

K. S. Smith and C. Ingram-Smith. 2007. Methanosaeta, the abandoned aceticlastic methanogen. Trends in Microbiology 15:150-5.

C. Ingram-Smith and K. S. Smith. 2007. AMP-forming acetyl-CoA synthetases in Archaea show unexpected diversity in substrate utilization. Archaea 2: 95-107.

C. Ingram-Smith, B. I. Woods, and K. S. Smith. 2006. Characterization of the acyl substrate binding pocket of acetyl-CoA synthetase. Biochemistry 45: 11482-11490.

C. Ingram-Smith, S. R. Martin, and K. S. Smith. 2006. Acetate kinase: not just a bacterial enzyme. Trends in Microbiology 14: 249-253.

C. Ingram-Smith, A. Gorrell, S. Lawrence, P. Iyer, K. S. Smith, and J. G. Ferry. 2005. Identification of the acetate binding pocket in the Methanosarcina thermophila acetate kinase. Journal of Bacteriology 187: 2386–2394.

Additional Publication Resources