This module discusses the activity of enzymes: the chemistry involved with cofactors, the chemical consequences of interactions of multiple enzymes in biochemical pathways, primary metabolism, the biosynthesis of secondary metabolites and applications in medicinal chemistry.

The module illustrates how fundamentals of chemical structure and reaction mechanisms can be applied to the detailed understanding of complex biological systems. Principles of enzyme catalysis and cofactor chemistry will be discussed. This will lead to the connection of multiple enzymatic reactions in metabolic pathways. Examples of biosynthesis of natural products from primary and secondary metabolism will be introduced. Concepts for interference with biochemical pathways in medicinal chemistry will be described.

1. discuss the differences between primary and secondary metabolism;
2. explain the physicochemical principles of enzyme catalysis;
3. illustrate the types of enzymatic transformation involved in primary and secondary metabolism;
4. discuss the chemistry of the cofactors TPP, NADH, FAD, PLP, SAM, ATP, biotin and CoA;
5. describe the intermediates and reactions of the glycolytic pathway, citric acid cycle, oxidative phosphorylation and pentose phosphate pathway;
6. outline the general biosynthetic pathways producing polyketide, terpenoid and alkaloid secondary metabolites;
7. explain why organisms produce secondary metabolites and display an appreciation of why some of these are of interest from a medicinal and economic perspective.

The module will be delivered in twenty-two 1-hour lectures, three 1-hour workshops and one 1-hour revision session.

On completion of the module a student should be able to:

Chemistry-specific skills

1. draw mechanisms for biochemical transformations using curly arrow notation;
2. propose biosynthetic pathways for previously unseen natural products;
3. design and interpret experiments for testing hypotheses regarding the biosynthetic origins of metabolites;
4. predict products and/or cofactor(s) of metabolic reactions given the structures of starting materials;
5. critically evaluate biosynthetic hypotheses based on evidence drawn from multiple sources.

Transferable Skills

1. use electronic and printed resources to extract relevant information;
2. report in writing on a topic studied;
3. solve problems, individually and as part of a group.

A written exam will test the student’s knowledge and understanding as elaborated under the learning outcomes. The coursework will allow the student to demonstrate his/her ability to judge and critically review relevant information.

Introduction to cofactors/coenzymes/prosthetic groups - metal ions, NADH, ATP, haem, flavins, PLP, thiamine, biotin, SAM.

Cofactors – mechanisms:

Flavins - dehydrogenases and oxidases (monoamine oxidase, acetylcoenzyme A dehydrogenase)

Pyridoxal phosphate - transaminases, decarboxylation of amino acids

Thiamine pyrophosphate - decarboxylation of alpha-keto acids.

Introduction to types of reactions in which these cofactors are involved - in terms of organic chemistry e.g. NADH = NaBH₄

Primary metabolism - glycolysis, citric acid cycle, oxidative phosphorylation, pentose phosphate pathway, reaction mechanisms and enzymes.

Fatty acid biosynthesis.

Secondary metabolites - biosynthesis of terpenes, alkaloids and polyketides.

Biosynthesis of aromatic amino acids.

Applications of secondary metabolites in medicine, agriculture and consumer products.

The Organic Chemistry of Biological Pathways, McMurry and Begley, Roberts & Co. ISBN 0-9747077-1-6

Chemical Aspects of Biosynthesis, Mann, OUP Primer, ISBN 0-19-855676-4

An Introduction to Enzyme and Coenzyme Chemistry, Bugg, Blackwell Science, ISBN 1405114525

Principles of Biochemistry, 5^th Ed., Nelson and Cox, Freeman, ISBN 0-7167-7108-X