Protein Function and Structure; Proteins and metalloenzymes; Vitamins and Trace Nutrient
Cytochrome P450 enzymes are powerful catalysts that play integral roles in biochemical pathways throughout nature. In mammals, members of this class of enzyme serve a variety of functions that include drug metabolism, steroid biosynthesis and the activation and deactivation of vitamin D, to name a few. Cytochrome P450 enzymes are also heavily involved in bacterial and plant biochemistry. The overall goal of our research is to use a combination of biochemical and biophysical tools to investigate structure and function in class I cytochrome P450 enzymes, thereby contributing toward an understanding of how this important class of enzymes work as well as informing the design of therapeutics. This goal is divided between two efforts. First, we are interested in characterizing the substrate and redox partner interactions of the enzyme CYP24A1, the P450 responsible for deactivating vitamin D. Describing the interaction between CYP24A1 and vitamin D has the potential to illuminate how the vitamin D structure becomes modified at a particular site. This insight could impact the design of vitamin D analogs with benefits for an array of human health conditions, including bone density disorders, diabetes and chronic kidney disease (CKD). A parallel effort in our group is a structural study of the enzyme CYP121 of Mycobacterium tuberculosis, the disease-causing pathogen in tuberculosis (TB). The resurgence of standard TB and the rise of drug-resistant forms of TB are quickly becoming a global pandemic, with TB claiming more lives worldwide in 2014 than HIV. CYP121 is essential for survival of the bacterium and thus has emerged as one of the more promising antitubercular drug targets. Students and postdocs joining my lab will be exposed to a multidisciplinary set of research tools, including expression and purification of recombinant membrane protein, nuclear magnetic resonance, protein X-ray crystallography and P450 ligand binding assays.
Structural Biology; X-ray Crystallography; Microbial Pathogenesis; Microbiology; Protein Function and Structure; Proteins and metalloenzymes
Our lab is interested in natural product biosynthesis and the fascinating proteins that bacteria use to make novel chemicals. We use a variety of techniques, including molecular and structural biology, as well as enzymology and other biophysical tools to understand protein structure and function. We are particularly interested in understanding the enzymatic basis for these biosynthetic pathways, as well as the role that novel compounds play in bacterial growth and pathogenesis.
Genomics and proteomics; Protein Function and Structure; Proteins and metalloenzymes
The Malkowski Laboratory is focused on understanding the structure and function of integral membrane enzymes involved in the conversion of lipid precursors into potent bioactive signaling molecules. We utilize a myriad of methods and techniques to characterize these enzymes, including X-ray crystallography, electron spin resonance spectroscopy, protein chemistry, biochemistry, molecular biology, cell biology, and kinetics.
Cell growth, differentiation and development; DNA Replication, Recombination and Repair; Gene Expression; Molecular and Cellular Biology; Proteins and metalloenzymes; Signal Transduction; Transcription and Translation
The main goal of my research group is to understand the role of N-terminal methylation on human development and disease. I identified the first eukaryotic N-terminal methyltransferases, NRMT1 and NRMT2, and am now working to identify how these enzymes and this new type of methylation affect cancer development and ageing. Our laboratory has shown that NRMT1 functions as a tumor suppressor in mammary glands, and its loss sensitizes breast cancer cells to DNA damaging chemotherapeutics. We have also created the first NRMT1 knockout mouse and shown it to have developmental defects, as well as, exhibit phenotypes of premature ageing. Currently, we are working to understand the exact biochemical pathways that lead from loss of N-terminal methylation to these phenotypes. We are also studying how post-translational modifications on the N-terminus of proteins may interact and dictate protein function, similar to the post-translational modifications found on histone tails.