Integrating Metabolism Flashcards
Energy Coupling
Energy produced by one reaction system or system is used to drive another.
Exergonic reactions (negative delta G) release energy
Endergonic reactions (positive delta G) absorb energy
ATP is usually the intermediary.
Catabolism and Anabolism
Anabolism is essentially reactions involving building things that require energy and catabolism reactions that generally break down things and release energy.
Anabolism is often reductive and energy-requiring.
Catabolism are often oxidative and energy-releasing.
Oxidation of Acetyl CoA via the TCA cycle
The cycle turns: Acetyl CoA is consumed.
2 Carbons leave as CO2
GTP (Goes to ATP)
Reducing equivalents are 3 NADH and 1 FADH2 which go into oxidative phosphorylation.
Metabolic Pathways
Carbohydrates:
Glycolysis & glucose oxidation (TCA cycle and ETC)
Gluconeogenesis
Glycogen synthesis & glycogenolysis
Fats:
Fatty acid oxidation
Lipogenesis
Proteins:
Amino acid catabolism
Carbohydrate Metabolism
Glucose-6-phosphate is also used in anabolic pathways:
Glycogen synthesis (starting from glucose-1-phosphate)
Nucleic acid synthesis (pentose phosphate pathway)
Biosynthesis of triglyceride (glycerol component)
Amino acid synthesis (from pyruvate and TCA cycle intermediates)
Cholesterol synthesis (from acetyl CoA)
Glycogen
Multibranched polysaccharide of glucose, a storage polymer mainly in muscle and liver.
Glucose units linked together linearly by a(1-4) glycosidic bonds, branching by a(1-6) glycosidic bonds.
Glycogen & Gluconeogenesis
Glycogenesis: from glucose-1-phosphate by glycogen synthase
Glycogenolysis: to glucose-6-phosphate by glycogen phosphorylase.
In muscle G6P enters glycolysis: important energy source in high-intensity, short-duration exercise.
Liver glucose-6-phosphatase generates glucose, which leaves cell and enters circulation, benefitting whole body.
Gluconeogenesis: synthesis of glucose from noncarbohydrate precursors (lactate, glycerol, amino acids)
Cori cycle is the lactic acid cycle: lactate produced by muscle glycolysis, transported to liver, converted to glucose, which returns to muscle.
Starvation: sacrifices muscle protein to make glucose for brain.
Fatty Acid Metabolism
Fatty acid supply
Lipolysis of stored triacylglycerol (=triglyceride)
Lipogenesis: de novo synthesis from Acetyl CoA
Fatty acid use:
Synthesis of triacylglycerol (esterification)
Beta-oxidation to Acetyl CoA
Ketogenesis
Fatty Acid Oxidation
Short and medium chain fatty acids enter the mitochondria directly
Long chain fatty acids shuttle into mitochondria using carnitine carrier.
Beta-oxidation of fatty acids
Acetyl CoA molecules in mitochondria then enters the beta-oxidation cycle
Each turn generates:
An acyl CoA 2 carbons shorter
Acetyl CoA
Reducing equivalent for the electron transport chain
Acetyl CoA then either generates ketone bodies or feeds into TCA cycle
Amino Acid Metabolism
Essential amino acids are supplied by diet
Non-essential amino acids derived from transamination
Excess amino acids are catabolized to urea via deamination.
Deaminated carbon skeletons are oxidized via TCA cycle
Amino Acids Catabolism
Mainly in the liver:
Removal of amino group to make urea
Carbon skeleton either oxidised to CO2 or H2O or used for gluconeogenesis or ketogenesis.
Nitrogen Metabolism
Amino acids (from ingested or endogenous protein) can be re-used for protein synthesis or catabolized.
Amino nitrogen enter urea by the liver urea cycle, then excreted in urine.
Amphibolic
A metabolic pathway that serves both as a catabolic and anabolic pathway
e.g. the TCA cycle is amphibolic
Anaplerosis
Anaplerosis: replenishment of TCAC intermediates.
Pyruvate carboxylase yields oxaloacetate
Glutamate dehydrogenase yields oxaloacetate
B-oxidation of odd-chain fatty acids yields succinyl CoA
Fed State
- Carbohydrates
- Glycolysis
- Glycogenesis
- Lipogenesis
- Synthesis of triglycerides from Fatty Acids
- Protein Metabolism
- Amino Acid Synthesis
Insulin is key signal
Fasted State
- Glycogenolysis source of glucose
- Gluconeogenesis supplies glucose to red blood cells and brain
- Lipolysis in adipose tissue release fatty acids and glycerol
- Glycerol converted to glucose via gluconeogenesis
- Increased oxidation of fatty acid and ketone bodies to supply energy, sparing glucose
- Ketosis arises as a result of deficiency of carbohydrates and utilization of fatty acids as an alternative fuel
- Protein catabolism, amino acids converted to glucose
Glucagon active, insulin suppressed.
Pathophysiology of metabolic integration
Inborn errors of metabolism:
Glycogen storage disorder: GSD1
Fatty acid oxidation defect: MCADD
Amino Acid Disorder: PKU
Urea Cycle Defect: OTCD
Nutritional pathology:
Diabetes: DKA
Malnutrition/Anorexia nervosa
Glycogen Storage Disorder Type I
Defective Glucose-6-phosphatase prevents glucose-6-phosphate from being converted to glucose
Causes accumulation of glycogen
Fatty Acid Oxidation Disorder: MCADD
Medium chain acyl dehydrogenase converts C8 acyl CoAs into C6 acyl CoAs
MCAD deficiency leads to accumulation of C8 acyl CoAs and deficiency of ketone production in starvation: ‘hypoketotic hypoglycaemia’
Amino Acid Disorder: Phenylketonuria
Phenylalanine is essential amino acid, converts to tyrosine by phenylalanine hydroxylase (PAH)
Deficiency of PAH causes toxic levels of phenylalanine to accumulate, causing progressive mental retardation and spasticity.
Phenylketonuria (PKU) named for metabolites excreted in urine.
Urea Cycle Disorder: OTC deficiency
Nitrogen enters the urea cycle carabamyl phosphate (made from ammonia) and leaves as urea (excreted)
Ornithine transcarbamylase is how carbamyl phosphate enters
OTC deficiency (X-linked) -> hyperammonaemia soon after birth (complete deficiency) or in stress/disease (partial deficiency).
Diabetic Ketoacidosis
Relative or absolute insulin deficiency stimulates hepatic glucose production
Hyperglycaemia causes osmotic diuresis and dehydration
Liver production of ketone bodies (B-hydroxybutyrate & acetoacetate) leads to hyperketonaemia and acidosis
A resemblance to starvation response.
