Ross, Matthew

Matthew K. Ross, B.S., Ph.D.

Associate Professor
Department of Basic Sciences

Contact Information
College of Veterinary Medicine
P.O. Box 6100
Mississippi State, MS 39762-6100
Phone: 662-325-5482
Fax: 662-325-1031
Email: This email address is being protected from spambots. You need JavaScript enabled to view it.

  • B.S., Chemistry
    University of California at Berkeley
  • Ph.D., Molecular Toxicology
    University of California at Irvine
  • Postdoctoral fellow
    Curriculum in Toxicology,
    University of North Carolina at Chapel Hill 

I was trained in chemistry and toxicology as an undergraduate, graduate student, and postdoc.  I have expertise in the following areas: bioanalytical chemistry (including liquid chromatography-mass spectrometry), drug and lipid metabolism, and the impact of environmental toxins on signal transduction pathways in cells.  As a faculty member at Mississippi State University (MSU), my focus has been on the carboxylesterase enzymes because of their important roles in xenobiotic and endobiotic metabolism, including an ability to hydrolyze the lipids cholesterol esters, endocannabinoids, and prostaglandin glyceryl esters.  My research program includes studies on carboxylesterase enzymology, gene regulation, cell physiology, and human interindividual variation in carboxylesterase activity.  Through our studies on carboxylesterases, we characterized other serine hydrolases (e.g., palmitoyl protein thioesterase 1) that also participate in endocannabinoid degradation.  In addition, I have initiated a lipidomics program at MSU to analyze bioactive lipids that are involved in inflammation and oxidative stress, such as prostaglandins, endocannabinoids, prostaglandin glyceryl esters, and isoprostanes in various tissues and biofluids by LC-MS/MS. My research is currently funded by the NIH (1R15ES015348-02).

Carboxylesterases: A multifunctional enzyme involved in xenobiotic and lipid metabolism

Carboxylesterases (CES, EC are members of the large α,β-serine hydrolase superfamily, which include proteases, lipases, and cholinesterases. CES catalyze the hydrolysis of several pesticides and drugs (xenobiotics) in mammalian species, thus they are important determinants of the pharmacokinetic behavior of xenobiotics in many organisms (Ross and Crow, 2007). CES are often termed non-specific esterases due to their broad substrate specificity, which is attributed to a large conformable active site that permits the entry of numerous structurally diverse substrates, including endobiotics and xenobiotics. Pyrethroids, organophosphates (OPs), and carbamates are insecticides used throughout the world and have essential roles in agriculture and public health. These chemicals possess carboxylester, phosphotriester, and carbamoyl bonds that are susceptible to hydrolysis, which accounts in part for their environmental and metabolic lability. Pyrethroids and organophosphates are the main classes of pesticides used in the U.S., and humans are exposed to these compounds on a daily basis. CES can metabolize and detoxify pesticides (e.g., pyrethroids and carbamates) by hydrolyzing ester and/or carbamoyl bonds (Ross et al., 2010); whereas, CES are inactivated by bioactive oxon metabolites of OP chemicals via covalent modification of the catalytic serine residue (Crow et al., 2012). Consequently, hydrolytic metabolism of ester-containing therapeutic drugs, narcotics, and pesticides by CES is a critical route of detoxication in humans, whereas inhibition of CES function may negatively impact normal cell physiological processes, as we have shown for cholesterol mobilization from macrophage foam cells (Crow et al., 2008). Therefore, obtaining new knowledge of CES function is important for clarifying the risk posed to human health following exposures to pesticides and drugs.

Although the role of CES in the metabolism and detoxication of xenobiotics is firmly established, the role of these enzymes in lipid metabolism is currently under scrutiny. For example, our laboratory recently showed that human CES can efficiently metabolize an endogenous cannabinoid receptor ligand, 2-arachidonoylglycerol (2-AG), and its cyclooxygenase-derived metabolites, termed prostaglandin glyceryl esters (Xie et al., 2010). Progress in the development of novel therapies based on the endocannabinoid system is in part dependent on our understanding of the metabolic pathways that regulate the endocannabinoid tone in vivo.

CES appears to be an example of a ‘catalytically promiscuous’ enzyme that acquired adventitious secondary activities (hydrolysis of neutral fatty acyl esters) apart from its main function, which is to detoxify diet-derived ester-containing toxins that animals were exposed to during their evolutionary history. Our laboratory continues to study the physiological roles of CES; characterize the chemico-biological interactions that occur between chemical inhibitors and carboxylesterase proteins; examine interactions between xenobiotics and lipids that occur at the level of the CES enzyme (e.g., endocannabinoid biochemistry); and attempt to integrate these findings within the context of diseases (e.g, atherosclerosis) that exhibit alterations in lipid metabolism and inflammation.

Characterization of other serine hydrolases with roles in endocannabinoid degradation

The profiles of serine hydrolases in human and mouse macrophages are similar yet different. For instance, human macrophages express high levels of carboxylesterase 1 (CES1), whereas mouse macrophages have minimal amounts of the orthologous murine CES1. On the other hand, both species’ macrophages exhibit limited expression of the canonical 2-arachidonoylglycerol (2-AG) hydrolytic enzyme, MAGL. 2-AG is an endogenous cannabinoid with several well-characterized roles in health and disease. Our previous study showed carboxylesterase 1 (CES1) was partly responsible for the hydrolysis of 2-AG (50%) and prostaglandin glyceryl esters (PG-Gs) (80-95%) in human THP1 monocytes/macrophages. However, MAGL and other endocannabinoid hydrolases, FAAH, ABHD6 and ABHD12, did not have a role because of either limited or no expression. Thus, another enzyme was hypothesized to be responsible for the remaining 2-AG hydrolysis activity following chemical inhibition and immunodepletion of CES1 (previous study) or CES1 gene knockdown (this study). We identified two candidate serine hydrolases in THP1 cell lysates by activity-based protein profiling (ABPP)–MudPIT and western blotting: cathepsin G and palmitoyl protein thioesterase 1 (PPT1). Both proteins exhibited similar electrophoretic properties to a serine hydrolase in THP1 cells detected by gel-based ABPP at 31-32 kDa; however, only PPT1 exhibited lipolytic activity and hydrolyzed 2-AG in vitro. Interestingly, PPT1 was highly expressed in THP1 cells but was significantly less reactive than cathepsin G toward the activity-based probe, fluorophosphonate-biotin. KIAA1363, another serine hydrolase, was also identified in THP1 cells but did not have significant lipolytic activity. On the basis of chemoproteomic profiling, immunodepletion studies and chemical inhibitor profiles, we estimated that PPT1 contributed 32-40% of 2-AG hydrolysis activity in the THP1 cell line. In addition, pure recombinant PPT1 catalyzed the hydrolysis of 2-AG, PGE2-G and PGF2α-G, although the catalytic efficiency of 2-AG hydrolysis by PPT1 was ~10-fold lower than CES1’s. PPT1 was also insensitive to several chemical inhibitors that potently inhibit CES1, such as organophosphate poisons and JZL184. Our studies are the first to document the expression of PPT1 in a human monocyte/macrophage cell line and to show PPT1 can hydrolyze the natural substrates 2-AG and PG-Gs. These findings suggest that PPT1 may participate in endocannabinoid metabolism within specific cellular contexts, and highlights the functional redundancy often exhibited by enzymes involved in lipid metabolism.

References cited:

Crow J.A., Middleton B.L., Borazjani A., Hatfield M.J., Potter P.M., Ross M.K. (2008) Inhibition of carboxylesterase 1 is associated with cholesteryl ester retention in human THP-1 monocyte/macrophages. Biochim. Biophys. Acta (Molecular and Cell Biology of Lipids) 1781, 643-654.

Crow J.A., Bittles V., Herring K.L., Borazjani A., Potter P.M., Ross M.K. (2012) Inhibition of Recombinant Human Carboxylesterase 1 and 2 and Monoacylglycerol Lipase by Chlorpyrifos Oxon, Paraoxon and Methyl Paraoxon. Toxicol. Appl. Pharmacol. 258, 145–150.

Ross M.K. and Crow J.A. (2007) Role of carboxylesterases in xenobiotic and endobiotic metabolism. J. Biochem. Mol. Toxicol. 21, 187-196.

Ross M.K., Streit T.M., Herring K.L., Xie S. (2010) Carboxylesterases: Dual roles in lipid and pesticide metabolism. J. Pest. Sci. 35, 257-264.

Xie S., Borazjani A., Hatfield M.J., Edwards C.C., Potter P.M., Ross M.K. (2010) Inactivation of lipid glyceryl ester metabolism in human THP1 monocytes/macrophages by activated organophosphorus insecticides: Role of carboxylesterase 1 and 2. Chem. Res. Toxicol. 23, 1890-1904.