Chapter 22: Biochem

• The major metabolic pathways for glucose, fatty acids, and amino acids center on pyruvate and acetyl-CoA

  
• Glycolysis


  The metabolic degradation of glucose begins with its conversion to two molecules of pyruvate with the net generation of two molecules of ATP

  
• Gluconeogenesis


  Mammals can synthesize glucose from a variety of precursors, such as pyruvate, via a series of reactions that largely reverse the path of glycolysis

  
• Glycogen degradation and synthesis


  The opposing processes catalyzed by glycogen phosphorylase and glycogen synthase are reciprocally regulated by hormonally controlled phosphorylation and dephosphorylation
• Fatty acid synthesis and degradation

  Fatty acids are broken down through β oxidation to form acetyl-CoA, which, through its conversion to malonyl-CoA, is also the substrate for fatty acid synthesis
• Citric acid cycle

  Oxidizes acetyl-CoA to CO2 and H2O with the concomitant production of reduced coenzymes whose reoxidation drives ATP synthesis
• Oxidative phosphorylation


  Mitochondrial pathway that couples the oxidation of NADH and FADH2 produced by glycolysis, β oxidation, and the citric acid cycle to the phosphorylation of ADP
• Amino acid synthesis and degradation

  Excess amino acids are degraded to metabolic intermediates of glycolysis and the citric acid cycle, with the amino group disposed of through urea synthesis. Nonessential amino acids are synthesized via pathways that begin with common metabolites
• Pyruvate and acetyl-CoA occupy central positions in mammalian fuel metabolism
• Only a few tissues, notably liver, can carry out all the reactions shown in Fig. 22-1, and in a given cell only a small portion of all possible metabolic reactions occur at a significant rate

  
• About 60% of all metabolic enzymes, representing essential "housekeeping" functions, are expressed at some level in all tissues in the human body
• Liver is the most metabolically active tissue, followed by adipose tissue and skeletal muscle

  
• The brain constitutes only 2% of the adult body mass but is responsible for 20% of its resting O2 consumption
• A blood glucose concentration of less than half the normal value can cause brain dysfunction and coma
• Skeletal muscle at rest uses 20% of the O2 consumed by the human body, and its respiration rate may increase in response to a heavy workload by as much as 25-fold
• Under conditions of maximum exertion, muscle must shift to ATP production via glycolysis of G6P, a process whose maximum flux greatly exceeds those of the citric acid cycle and oxidative phosphorylation
• Much of the G6P is degraded anaerobically to lactate, and export of lactate relieves much of the muscle's respiratory burden
• Muscle fatigue occurs after prolonged, intense exercise due to the accumulation of lactic acid and the depletion of phosphocreatine and glycogen stores
• Aerobic metabolism of fatty acids and ketone bodies is more efficient than glycolysis alone in providing ATP during exercise of varying duration
• ATP regeneration

  1. Phosphocreatine reacts with ADP

  2. Phosphocreatine resynthesized in resting muscle by reversal of this reaction
• Under conditions of maximum exertion, a muscle has only about a 4-s supply of phosphocreatine
• ATP production during maximum exertion

  1. Glycolysis of G6P

  2. Much of the G6P degraded anaerobically to lactate
• Export of lactate

  Relieves much of the muscle's respiratory burden
• Muscle fatigue occurs after the phosphocreatine supply is depleted and glycolysis becomes less efficient than oxidative phosphorylation
• Heart muscle


  • Relies entirely on aerobic metabolism
  • Richly endowed with mitochondria (up to 40% of cytoplasmic space)
  • Can metabolize fatty acids, ketone bodies, glucose, pyruvate, and lactate
  • Fatty acids are the resting heart's fuel of choice, but during heavy work greatly increases glucose consumption

  
• Adipose tissue


  • Stores and releases fatty acids as needed for fuel
  • Secretes hormones involved in regulating metabolism

  
• A normal 70-kg man's adipose tissue contains a large amount of fatty acids
• Glucokinase


  • Has much lower affinity for glucose than hexokinase
  • Exhibits sigmoidal rather than hyperbolic variation with glucose concentration
• Glucokinase is subject to metabolic control by a glucokinase regulatory protein that inhibits it in the presence of fructose-6-phosphate
• Fructose-1-phosphate overcomes this inhibition, so fructose may be the signal that triggers the uptake of dietary glucose by the liver

  
• Fates of glucose-6-phosphate in the liver

  1. Converted to glucose for transport to peripheral organs

  2. Converted to glycogen

  3. Enters glycolysis

  4. Enters pentose phosphate pathway

  
• Liver cannot use ketone bodies as fuel because it lacks 3-ketoacyl-CoA transferase
• Fatty acid metabolism in the liver

  1. Degraded to acetyl-CoA and ketone bodies for export to peripheral tissues when demand for metabolic fuels is high

  2. Incorporated into triacylglycerols and secreted as VLDL when demand for metabolic fuels is low

  
• Amino acids are important metabolic fuels, providing a significant fraction of energy immediately after a meal and during fasting
• Kidney


  • Filters urea and other waste products from blood
  • Recovers important metabolites like glucose
  • Maintains blood pH by regenerating depleted buffers and excreting excess acids
• Cori cycle

  1. Lactate produced by muscle glycolysis is transported to liver

  2. Liver converts lactate to glucose by gluconeogenesis

  3. Glucose is transported back to muscle

  
• Cori cycle operates


  After vigorous exertion, to pay off oxygen debt created by demand for ATP to drive gluconeogenesis
• Glucose-alanine cycle

  1. Alanine transported from muscle to liver

  2. Liver converts alanine back to pyruvate, which is used for gluconeogenesis

  3. Glucose is transported back to muscle

  
• Pyruvate and acetyl-CoA are important for both catabolism and anabolism
• High KM of glucokinase is important for liver's role in buffering blood glucose