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Lecture 12

BIOC13Winter2013 Lecture 12 Notes.docx

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Biological Sciences
Daman Bawa

BIOC13Winter2013 Lecture 12: Amino acid metabolism and metabolic integration Amino acid Metabolism o Plants and bacteria synthesize all twenty amino acids, humans can only synthesize about half of the twenty amino acids (non-essential AAs). Rest must be acquired from dietary sources o In general, the more complex amino acids are essential amino acids in humans as they require enzymes that have been lost from the human genome over evolutionary time. o In animals, proteases present in stomach and intestines cleave the peptide bond to yield amino acids and small oligopeptides o The carbon skeletons of all twenty amino acids are derived from just seven metabolic intermediates: o three glycolytic pathway intermediates: 3-phosphoglycerate, phosphoenolypyruvate, and pyruvate o two pentose phosphate pathway intermediates: ribose 5-phosphate and erythrose 4-phosphate o two citrate cycle intermediates: -ketoglutarate and oxaloacetate Protein Degradation o o Free amino acids in the body can be generated by degradation of cellular proteins which occurs continuously in all cells. Most eukaryotic cellular proteins are degraded by one of two pathways: o an ATP-independent process that degrades proteins inside cellular vesicles called lysosomes o an ATP-dependent pathway that targets specific proteins for degradation in proteasomes if they contain a polymer of ubiquitin protein covalently attached to lysine residues. o In order for proteins to be degraded by the proteasome, they are first "tagged" on lysine residues by covalent linkage of ubiquitin. Ubiquitin is a 76 amino acid protein found in all eukaryotic cells that is specifically attached to proteins by ubiquitin ligating enzymes. o The proteins are cleaved by endo and exo-proteases/peptidases to individual amino acids Amino acid degradation o Most AAs are de-aminated first by a process called transamination which basically transfers the amino group to an a-keto acid to yield an a-keto acid of the original AA and a new AA o a-ketoglutarate is the main amino acid acceptor and yields glutamate and a keto acid o Glutamate’s amino group can be transferred to oxaloacetate in a second transamination reaction, yielding Aspartate and reforming a-ketoglutarate o Transamination is catalyzed by enzymes called aminotransferases or transaminases which require a coenzyme called Pyridoxal-5’-phosphate (PLP) The Urea cycle o Glutamate and glutamine function as the primary nitrogen carriers in most organisms. In mammals, this nitrogen ends up in the liver where it is converted to urea. o The two nitrogens in urea are derived from the 4H released when glutamate or glutamine are deaminated, and from aspartate which is formed when oxaloacetate is transaminated by aspartate aminotransferase. o The carbon atom in urea comes from CO2(HCO 3 that is produced in the mitochondrial matrix by the citrate cycle (the oxygen atom is derived from 2 O in the final reaction of the cycle). o Urea synthesis provides an efficient mechanism for land animals to remove excess nitrogen from the body. Urea is synthesized in the liver and exported to the kidneys where it enters the bladder. Amino acid biosynthesis 1 o o Arginine is listed as an essential amino acid because humans require arginine in their diet to support rapid growth during childhood and pregnancy, even though it is made by urea cycle. o Tyrosine is also highlighted because this conditional nonessential amino acid is made in humans from the essential amino acid phenylalanine. o In general, the structures of the essential amino acids are more complex than the nonessential amino acids which is reflected in the number of enzymatic reactions required for synthesis o Metabolic flux through various amino acid biosynthetic pathways is tightly regulated by feedback inhibition to provide the required proportions of each amino acid in response to cellular needs. o o amino acids are precursors for a number of biomolecules o heme comes from glycine and acetate o purines and pyrimidines o hormones and NTs synthesized by decarboxylation and hydroxylation of histidine, glutamate, tryptophan and tyrosine o oxidation of arginine = NO which is signaling molecule in cells o melanin o Numerous diseases are caused by defects in amino acid metabolic pathways; some of these diseases are genetic diseases and can be due to recessive or dominant mutations of key enzymes in the pathways. Metabolic Integration Metabolic Homeostasis 2 o Metabolic homeostasis describes steady-state conditions in the body and can apply to a wide variety of physiological parameters. o These include glucose, lipid, and amino acid levels in the blood, electrolyte concentrations, blood pressure and pulse rate. o During times of physical activity, psychological stress, or feeding, biochemical processes are altered to counteract the effects of these environmental stimuli in an attempt to return the body to metabolic homeostasis. o Regulation of metabolic homeostasis requires both neuronal signaling from the brain and the release of small molecules into the blood that function as ligands for receptor-mediated cell signaling pathways. o Disturbances in metabolic homeostasis leads to metabolic diseases such as diabetes. o Flux through pathways depend on presence of appropriate enzymes and organismal/cell needs  liver can carry out all the learned pathways Cellular Regulation of Metabolism o Substrate availability o Supply and demand o Allosteric and feedback control o 5’ AMP kinase (AMPK) o Intracellular control in response to energy demands o Hormonal/cytokine regulation o Multi-organ control o Response to serum levels of metabolites and metabolic state of body Metabolic integration through tissue specialization o Metabolic pathways are specialized in the tissues o Brain  transports ions to maintain membrane potentials, inegrates inputs from body and surrounding, sends signals to other organs o Liver  processes fats, carbs, proteins ; synthesizes and distributes lipids, ketone bodies and glucose; converts excess N to urea o Skeletal muscle  uses ATP to do mechanical work o Cardiac muscle  supplies body with blood (i.e oxygen and nutrients) o Adipose Tissue  synthesizs and stores and mobilizes triacylglycerols Metabolism in Brain o Fuel reserves: Very little to none o Metabolism: o Strictly aerobic o Very high metabolism (consumes 20% of total energy) o Needs a constant supply of glucose from the blood (120g/day) o Fuel: Glucose o Fasting conditions: the brain can use Ketone bodies, but still requires carbohydrates (may also use lactic acid) o Long chain FAs cannot cross the blood brain barrier because they are bound to the carrier proteins o Fuel exported: None Metabolism in Muscle Cells o Fuel reserve: glycogen (P-creatine), some FAs o Metabolism: o at rest – aerobic o vigorous activity – anaerobic o Preferred Fuel: Fatty acids, glucose when active o Muscles must be prepared for rapid provision of energy o Creatine kinase and phosphocreatine act as a buffer system, providing additional ATP for contraction o Glycogen provides additional energy, releasing glucose for glycolysis o Glycolysis rapidly lowers pH, causing muscle fatigue o Fuel exported: Lactate, alanine, glutamine o Hormones: Insulin, adrenaline Effects of exercise o Short, vigorous (eg 100 m sprint) o Free ATP  P-creatine  glycolytic ATP o blood lactate increases and blood pH decreases. Acidosis causes fatigue. o Longer duration(eg, 1000 m run) o aerobic  oxidation of muscle glycogen - energy produced at a slower rate. o Very long periods of exercise (eg. marathon) o liver glycogen supply – (even slower rate of supply) 3 o Glycogen stores are insufficient to provide fuel required for marathon (require 150 mols ATP, glycogen ≈ 105 mols). o Fat reserves – (slowest rate of energy production) o Ketogenesis (generally only in conditioned athletes) o Protein breakdown - This is a fuel of last resort for the fasting or exhausted organism Metabolism in Cardiac Muscles o Due to continuous contractions, the cardiac o muscles rely on aerobic metabolism o Cells have high number of mitochondria (~40% of the cytoplasmic space) o Heart can metabolize a number of energy sources: fatty acids, ketone bodies, glucose, pyruvate and lactate o Under resting conditions fatty acids are the fuel of choice o Under exercise conditions (increased heart rate), glucose derived from limited glycogen stores in the cells is used as a primary source for the energy. Metabolism in Adipose tissue o Fuel reserve: TAGs, some glycogen o Metabolism: aerobic o Preferred fuel: fatty acids, glucose o Fuel exported: fatty acids, glycerol o Hormones: insulin, Glucagon, adrenalin o TAGs may account for as much as 65% of weight of fat cell. o Receives exogenous TAGs in chylomicron from intestinal system (via lymphatic system and bypass liver) o High blood glucose - glucose used for FA and TAG synthesis (FFAs from liver) o Cells require a source of glucose to make TAGs (lacks glycerol kinase) o Active player in metabolic integration serving as an endocrine organ t
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