metabolism and regulation of intermediary metabolites · aim of this presentation • to discuss...
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Metabolism and Regulation of Intermediary Metabolites
Dr Mick HendersonBiochemical GeneticsLeeds Teaching Hospitals Trust
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Aim of this presentation
• To discuss principles of metabolic control
• Outline main metabolic categories• Discuss co-operation and regulation
between organs and pathways
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What is metabolism?
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Intermediary Metabolism
• energy pathways• biosynthetic pathways• miscellaneous
– Degradative– Detoxifying– Redox
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Energy generating pathways
• Glycolysis• Gluconeogenesis• Glycogen storage and breakdown• Fatty acid oxidation• Ketone synthesis and metabolism• Amino acid catabolism• Krebb’s cycle• Oxidative phosphorylation
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Biosynthetic pathways
E.g.• haem• neurotransmitters
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Miscellaneous pathways
• Urea cycle – detoxifying• Pentose phosphate pathway –
generates reducing equivalents• Glutathione synthesis• Anaplerotic pathways
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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
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Short/medium term control
Gene expression• Protein synthesis
– e.g. haem is genetic regulator of transcription of synthetic enzymes
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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
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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
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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
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Post prandial carbohydrate metabolism
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Post prandial amino acid metabolism
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Muscle shares metabolic load with liver
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Acetyl CoA, a key metabolite
How is futile cycling prevented?• Glycolysis and gluconeogenesis• Fat oxidation and fatty acid synthesis
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Anaplerosis and cataplerosis
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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
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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
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And finally
This is what its all about:
Reproductionand then………….
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