The Molecular Basis Of Cytochrome P450 And UDP-glucuronosyltransferase Isoform Substrate Selectivity
Funder
National Health and Medical Research Council
Funding Amount
$448,500.00
Summary
Drugs and chemicals (e.g. dietary constituents, environmental pollutants and industrial chemicals) are broken down in the body by specific enzymes, a process referred to as metabolism. Drug and chemical metabolism serves as a detoxification mechanism (since the end products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. Enzymes are highly specialised proteins made up from amino acids as the building blocks. There are two enzymes in ....Drugs and chemicals (e.g. dietary constituents, environmental pollutants and industrial chemicals) are broken down in the body by specific enzymes, a process referred to as metabolism. Drug and chemical metabolism serves as a detoxification mechanism (since the end products of metabolism generally lack biological activity) and as a means of eliminating these substances from the body. Enzymes are highly specialised proteins made up from amino acids as the building blocks. There are two enzymes in humans primarily responsible for the metabolism of drugs and other chemicals; cytochrome P450 (CYP) and UDP-glucuronosyltransferase (UGT). Indeed, CYP and UGT are together responsible for the elimination of over 90% of metabolised drugs in humans. Both UGT and CYP exist as superfamilies of structurally related enzymes (called 'isoforms'). Approximately fifteen CYP isoforms are known to metabolise drugs, and a similar number of UGT isoforms also appear to have the capacity to metabolise drugs in humans. The separate CYP and UGT isoforms preferentially metabolise different types of drugs and chemicals, due to the fact each isoform comprises a different sequence of amino acids. However, which of the approximately 500 amino acids present in each UGT and CYP isoform that bind and metabolise specific drugs and chemicals is unknown. This project will identify the individual amino acids of several important CYP and UGT isoforms responsible for binding and metabolising drugs and other chemicals. A variety of techniques will be used, including modification of the amino acid sequence of the isoforms and computer modelling of their 'internal' structure. Elucidating the structural basis of how drugs and chemicals interact with CYP and UGT isoforms is fundamental to our understanding of these important enzymes and their function, and can be used to design drugs with better metabolic stability and decreased propensity for troublesome interactions with other drugs.Read moreRead less
The aim of this proposal is to evaluate a novel therapy option for children with a genetic disorder called mucopolysaccharidosis (MPS). MPS arise from the build up of complex carbohydrates in cells within the body due to the deficiency of an enzyme required for their degradation. By decreasing the synthesis of carbohydrate we can manipulate the level of stored carbohydrate and alleviate the pathology associated with MPS. The novel therapy is based on a chemical modification of glucose that inhib ....The aim of this proposal is to evaluate a novel therapy option for children with a genetic disorder called mucopolysaccharidosis (MPS). MPS arise from the build up of complex carbohydrates in cells within the body due to the deficiency of an enzyme required for their degradation. By decreasing the synthesis of carbohydrate we can manipulate the level of stored carbohydrate and alleviate the pathology associated with MPS. The novel therapy is based on a chemical modification of glucose that inhibits carbohydrate synthesis and is termed substrate deprivation therapy.Read moreRead less
Proteases are enzymes that degrade other proteins. These molecules are essential for life and drive fundamental processes such as blood clotting and the inflammatory response. Protease dysfunction underlies numerous human diseases, including cancer. This proposal aims to investigate whether structural information can be used to improve our ability to accurately predict the target specificity of proteases.