Lecture 27. Introduction to metabolism
Monday 14 November 2016
Principles and background knowlegde relevant to metabolism. Introduction to glycolysis and other metabolic pathways. Impotance of thermodynamics and regulatory principles. Acetyl CoA and thioesters.
Reading: VVP4e - Ch.14, pp.436-461.
Summary
The study of metabolism draws heavily upon enzymology, thermodynamics, organic chemistry, is informed by various levels of biology frrom molecular to organismal, and is concerned not only with the sequence of biochemical reactions of metabolic pathways, but also the means and mechanisms by which they are regulated, as well as their integration into a living organism as an autonomous complex system.
A systematic treatment of metabolic pathways invariably begins with glycolysis. The glycolytic pathway formally begins with glucose, which is phosphorylated and then isomerized to fructose 6-phosphate. In the case of animals or humans, glucose metabolism is integrated with the storage and breakdown of glycogen. Alongside of glycolysis, it is necessary to consider its formal reverse, the pathway of gluconeogenesis.
To assist with a beginning to as well as a comprehensive understanding of glycolysis, below is a summary of useful background and relevant related knowledge with some links and additional textual sources:
Carbohydrates: Simple carbohydrates (monosaccharides). Pentoses and hexoses. Furanose and pyranose rings and their conformations. Complex carbohydrates. (See VVP 4e - Ch.8, epecially pp.217-230.)
Organic chemistry and logic of the glycolytic pathway. Application of carbonyl chemistry to glycolytic reactions converting glucose to glyceraldehyde 3-phosphate (GAP). Keto-enol tautomerizations, formation of enolates, aldol condensation are all featured in the reactions of glycolysis.
Biochemical thermodynamics. The energy content of various phosphorylated metabolites (ATP, 1,3-bisphosphoglycerate, phosphoenolpyruvate) as measured by biochemical standard free energy of hydrolysis (also called phophoryl transfer potential). The process of substrate-level phosphorylation. Biochemical redox reactions and the free energy available in oxidation of metabolites. (See VVP 4e - Ch.14, pp.446-456.)
Regulation. Regulation of enzyme activity by allosteric effects and reversible covalent modification (phosphorylation/dephosphorylation). Regulation of the regulators: Hormones and signal transduction pathways. Insulin, glucagon, and epinephrine. Heterotrimeric G proteins, adenylate cyclase, the "second messenger" (cAMP), and cAMP-dependent protein kinase, which is also commonly referred to as protein kinase A (PKA). Thermodynamics and control of metabolic flux (VVP 4e - Ch.14, pp.443-446).
Glycogen metabolism. Structure of glycogen. Metabolic consumption of glycogen by phosphorolysis, catalyzed by glycogen phosphorylase (often referred to as "phosphorylase"). Glycogen synthesis. Regulation of glycogen metabolism (VVP 4e - Ch.8, pp.227-228; Ch.12, pp.381-385; Ch.16, pp.518-538).
Gluconeogenesis. The gluconeogenic pathway. Reciprocal regulation of glycolysis and gluconeogenesis (VVP4e - Ch.16, pp.538-545).
Acetyl CoA and thioesters
Coenzyme A, a carrier of acyl groups, contains an active thiol group that forms a thioester linkage with acyl groups constituitive of various acyl CoA species. The structure of coenzyme A shows that it is made up of an adenine nucleotide (AMP) linked to phosphopanthetheine, derived from the B vitamin pantothenate. Acetyl CoA, the thioester formed when the acyl group is acetate, is central to the oxidative metabolism of carbohydrates, as well as that of fatty acids and amino acids.