BIOCHEM 9: overview of metabolism

• Metabolism is the interconversion of chemical compounds in the body, the pathways taken by the individual molecules, their interrelationships, and the mechanisms that regulate the flow of metabolites through the pathways.
• Phenylalanine, Tyrosine, Tryptophan, Isoleucine yield both acetyl-CoA and intermediates that can be used for gluconeogenesis, and are referred to as ketogenic.
• Lysine and Leucine yield only acetyl-CoA on oxidation, and hence cannot be used for gluconeogenesis.
• Anabolic Pathways, involved in the synthesis of larger and more complex compounds from smaller precursors, are endergonic/endothermic.
• Catabolic Pathways, involved in the breakdown of larger molecules, commonly involving oxidative reactions, are exergonic/exothermic, producing reducing equivalents and mainly via the respiratory chain, ATP.
• The other major source of long-chain fatty acids is synthesis (lipogenesis) from carbohydrates, in adipose tissue and the liver.
• triacylglycerol is not taken up directly by the liver but is first metabolized by tissues that have lipoprotein lipase, releasing fatty acids that are incorporated into tissue lipids or oxidized as fuel.
• The chylomicron remnants are cleared by the liver.
• Many enzymes that degrade protein and polysaccharides reside in lysosomes.
• Many apparently antagonistic pathways can coexist in the absence of physical barriers provided that thermodynamics dictates that each proceeds with the formation of one or more unique intermediates.
• Compartmentation ensures metabolic efficiency and simplifies regulation.
• Fatty acid biosynthesis occurs in the cytosol, whereas fatty acid oxidation takes place within mitochondria.
• Reesterification of monoacylglycerol and fatty acids occurs in the small intestine, which are packaged with protein and secreted into the bloodstream as chylomicrons.
• Amphibolic pathway occurs at the “crossroads” of metabolism, acting as links between the anabolic and catabolic pathways.
• Intermediary Metabolism is applied to reactions involving low molecular weight molecules that are metabolites of degradation or biosynthesis of biopolymers.
• To establish control points – balance of energy supply and demands in the living cell, ability to respond to internal signals or change in the environment.
• Limited reaction – specificity of the enzymes; each active site catalyzes only a single step of the pathway
• Supply of substrates includes ATP, ADP, Hormones such as Insulin, Glucagon, Norepinephrine/Epinephrine.
• Regulation of Metabolite Flow tends to be Unidirectional in living cells, the reaction products of one enzyme-catalyzed reaction serve as substrates for, and are removed by, other enzyme-catalyzed reactions.
• To control energy input and output – energy flow is mediated by energy donors and acceptors
• Fat Metabolism is concerned mainly with fatty acids and cholesterol.
• Allosteric Modification includes Feedback Inhibition, when the product controls the rate of its synthesis, and Feedforward activation, when a metabolite produced early in the pathway activates an enzyme that catalyzes a reaction further down the pathway.
• Covalent Modification alters catalytic rate by attachment to some group by covalent bond (usually a phosphate group), examples include Phosphorylation, which activates enzymes regulating catabolic pathways and inhibits enzymes regulating anabolic pathways, and Dephosphorylation, which inhibits enzymes regulating catabolic pathways and activates enzymes regulating anabolic pathways.
• AA can be classified as glucogenic/ ketogenic,
• The ideal regulatory enzyme is one whose quantity or catalytic efficiency dictates that the reaction it catalyzes is slow relative to all others in the pathway.
• Excess carbohydrates can be converted to FA (TAGs; in both adipose tissue and liver), and Acetyl-CoA, which can never be used for gluconeogenesis.

  
  

  - any substrate that yields acetyl-CoA can never be used for gluconeogenesis
• Controlling an Enzyme that Catalyzes a Rate-limiting Reaction Regulates an Entire Metabolic Pathway.
• Catabolism of tissue fuels yield three types of compounds that mediates the release of energy: Acetyl CoA, Nucleoside triphosphate (ATP), Reduced coenzymes (NADH, FADH2).
• Fatty acids may be oxidized to acetyl-CoA via β-oxidation or esterified with glycerol, forming TRIACYLGLYCEROL.
• The liver regulates blood concentration of most water-soluble metabolites, including carbohydrates, fats, and amino acids.
• Acetyl-CoA is the precursor for synthesis of cholesterol and other steroids.
• The liver maintains an adequate concentration of blood glucose which is vital for those tissues in which it is the major fuel (the brain) or the only fuel (the erythrocytes).
• The liver synthesizes major plasma proteins (e.g., albumin) and deamines amino acids that are in excess of requirements, forming urea, which is transported to the kidney and excreted.
• Acetyl-CoA arising from glycolysis is oxidized to CO2 + H2O via the Citric Acid Cycle.
• Skeletal muscles store glycogen as a fuel for its use in muscular contraction and synthesize muscle protein from plasma amino acids.
• Skeletal muscles represent approximately 50% of body mass and consequently represent a considerable store of protein that can be drawn upon to supply amino acids for gluconeogenesis in starvation.
• Amino acids undergo two processes: Transamination, and Deamination, which also produces urea.
• Several amino acids are also the precursors of other compounds, such as purines, pyrimidines, hormones such as epinephrine and thyroxine, and neurotransmitters.
• Acetyl-CoA forms ketone bodies in the liver, which are important fuels during prolonged fasting and starvation: Acetone, Acetoacetate, 3-hydroxybutyrate.
• The fate of the carbon skeleton that remains after transamination can be oxidized to CO2 via the citric acid cycle, form glucose (gluconeogenesis), or form ketone bodies.