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………….