Integrating Metabolism

Question 1

Energy Coupling

Answer 1

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.

Question 2

Catabolism and Anabolism

Answer 2

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.

Question 3

Oxidation of Acetyl CoA via the TCA cycle

Answer 3

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.

Question 4

Metabolic Pathways

Answer 4

Carbohydrates:
Glycolysis & glucose oxidation (TCA cycle and ETC)
Gluconeogenesis
Glycogen synthesis & glycogenolysis

Fats:
Fatty acid oxidation
Lipogenesis

Proteins:
Amino acid catabolism

Question 5

Carbohydrate Metabolism

Answer 5

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)

Question 6

Glycogen

Answer 6

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.

Question 7

Glycogen & Gluconeogenesis

Answer 7

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.

Question 8

Fatty Acid Metabolism

Answer 8

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

Question 9

Fatty Acid Oxidation

Answer 9

Short and medium chain fatty acids enter the mitochondria directly
Long chain fatty acids shuttle into mitochondria using carnitine carrier.

Question 10

Beta-oxidation of fatty acids

Answer 10

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

Question 11

Amino Acid Metabolism

Answer 11

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

Question 12

Amino Acids Catabolism

Answer 12

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.

Question 13

Nitrogen Metabolism

Answer 13

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.

Question 14

Amphibolic

Answer 14

A metabolic pathway that serves both as a catabolic and anabolic pathway
e.g. the TCA cycle is amphibolic

Question 15

Anaplerosis

Answer 15

Anaplerosis: replenishment of TCAC intermediates.
Pyruvate carboxylase yields oxaloacetate
Glutamate dehydrogenase yields oxaloacetate
B-oxidation of odd-chain fatty acids yields succinyl CoA

Question 16

Fed State

Answer 16

• Carbohydrates
  
  • Glycolysis
  • Glycogenesis
  • Lipogenesis
  • Synthesis of triglycerides from Fatty Acids
  • Protein Metabolism
  • Amino Acid Synthesis
    Insulin is key signal

Question 17

Fasted State

Answer 17

• 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.

Question 18

Pathophysiology of metabolic integration

Answer 18

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

Question 19

Glycogen Storage Disorder Type I

Answer 19

Defective Glucose-6-phosphatase prevents glucose-6-phosphate from being converted to glucose
Causes accumulation of glycogen

Question 20

Fatty Acid Oxidation Disorder: MCADD

Answer 20

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’

Question 21

Amino Acid Disorder: Phenylketonuria

Answer 21

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.

Question 22

Urea Cycle Disorder: OTC deficiency

Answer 22

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).

Question 23

Diabetic Ketoacidosis

Answer 23

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.