Metabolism and Regulation of Intermediary Metabolites

Dr Mick HendersonBiochemical GeneticsLeeds Teaching Hospitals Trust

Aim of this presentation

• To discuss principles of metabolic control

• Outline main metabolic categories• Discuss co-operation and regulation

between organs and pathways

What is metabolism?

Intermediary Metabolism

• energy pathways• biosynthetic pathways• miscellaneous

– Degradative– Detoxifying– Redox

Energy generating pathways

• Glycolysis• Gluconeogenesis• Glycogen storage and breakdown• Fatty acid oxidation• Ketone synthesis and metabolism• Amino acid catabolism• Krebb’s cycle• Oxidative phosphorylation

Biosynthetic pathways

E.g.• haem• neurotransmitters

Miscellaneous pathways

• Urea cycle – detoxifying• Pentose phosphate pathway –

generates reducing equivalents• Glutathione synthesis• Anaplerotic pathways

How is it controlled?Long term control• Compartmentation

– Between organs • e.g. glucose 6 phosphatase expressed in liver but

not muscle– Within cells

• e.g. acid hydrolases transported to, and activated within, lysosomes

• Gene expression, varying between tissues• e.g. enzymes of the urea cycle predominantly

expressed in hepatic cells

• Iso enzymes• e.g. muscle and liver glycogen synthase, coded for

by distinct genes

Short/medium term control

Gene expression• Protein synthesis

– e.g. haem is genetic regulator of transcription of synthetic enzymes

haem synthesis

ALA PBG URO’gen 111 COPRO’gen 111

URO’gen 1 COPRO’gen 1

PROTO’gen

PROTO

HAEMFe

ALA synthetase

allostericand synthetic

regulation

HMB

Short/medium term control

Gene expression• Protein synthesis

– e.g. haem is genetic regulator of transcription of synthetic enzymes

Control of rate limiting steps• Transport across membranes• Mobilisation from storage• Controlled by hormones

Rapid control

Direct control of protein, enzyme, action• Phosphorylation

– e.g. glycogen phosphorylase activation

• Allosteric moderation– e.g. haem deactivates ALA synthase

• Competitive inhibition– e.g. acetyl CoA acetyl transferase is inhib by its product

acetoacetyl CoA (ketone syn)

• Translocation between subcellular locations– e.g recruitment of GLUT4 receptors to muscle and

adipose cell surface by insulin

Post prandial carbohydrate metabolism

Post prandial amino acid metabolism

Muscle shares metabolic load with liver

Acetyl CoA, a key metabolite

How is futile cycling prevented?• Glycolysis and gluconeogenesis• Fat oxidation and fatty acid synthesis

Anaplerosis and cataplerosis

Novel dysregulation

• Compound heterozygosity (Vockley JIMD)

– Increasing probability with no. steps in pathway

– Animal model with multiple heterozygosity for fat oxid. enzymes, mortality under stress + typical FAO metabs detectable in XS

• Intronic mutations

Key Sources

Metabolic RegulationA Human PerspectiveKeith Frayn2nd Edition 2003, Blackwell Science

See also;The key role of anaplerosis and cataplerosis for

citric acid cycle functionOwen OE et al, J Biol Chem; 2002, 34, 30439-12

And finally

This is what its all about:

Reproductionand then………….