Amino Acid Metabolism: Special Functions, Inherited Diseases PDF

Amino Acid Metabolism: Special Functions, Inherited Diseases Enzymes for AA Synthesis Essential AAs Non-Essential AAs • Expensive to synthesize • ?survival advantage to be able to rely on diet • Easy to synthesize • ?survival advantage to maintain capacity to synthesize • 59 enzymes total •...

Amino Acid Metabolism: Special Functions, Inherited Diseases Enzymes for AA Synthesis Essential AAs Non-Essential AAs • Expensive to synthesize • ?survival advantage to be able to rely on diet • Easy to synthesize • ?survival advantage to maintain capacity to synthesize • 59 enzymes total • 17 enzymes • Are they more important? Dispensable AAs Intake De novo synthesis Special Products Synthesis Free AA Pool Feces Urinary Nitrogen Breakdown CO2, H2O Body Protein Precursor-product relationship Plasma Proteins Diet Precursor Pool Glutathione Special products Tracer Enzymes Transporters…. Special Products Reeds 2000 Synthesis of dispensable AAs • High flux rates • High proportion from de novo synthesis • Synthesis accounts for up to 8% of basal metabolic rate • Ultimate precursor is glucose • Except for tyrosine • For cysteine – only the S is from methionine Cysteine Methionine Homocysteine Serine Cystathionine Cysteine Classical sulphur AAs Kinetic view of sulphur AAs See Fig 34.3 Issues in sulphur AA metabolism • Methylation reactions • Vitamins • Homocysteine • Liver function • Premature infants • Intravenous feeding • Taurine • Glutathione Glutathione (GSH) • γ-glutamyl-cysteinyl-glycine • intracellular • protection against oxidative stress • conjugation with electrophiles • removal of reactive oxygen species • glutathionylation of proteins • proteins, lipid membranes, DNA • immune system function • erythrocyte function Glutathione depletion Nutritional Status Inflammation/ Infection • short term fasting • burns • protein deficiency Synthesis < • AIDS Consumption Supplements? • Glutathione - no Acetominophen • • • • Generic: acetaminophen = paracetamol Trade Name: Tylenol ® Drug class: NSAID – non-steroidal anti-inflammatory drug Indications: Analgesic, Antipyretic, (Antiinflammatory minimal effect) • Toxicity • Toxic metabolite: NAPQI – hepatocellular damage, liver failure • Treatment: activated charcoal, N-acetylcysteine (GSH precursor)….liver transplant • Most common cause of drug overdose, and of liver failure • By The Sceptical Chymist - Own work, CC BY-SA 4.0, https://commons.wikimedia.org/w/index.php?curid=102845037 PHE hydroxylation to TYR recall the parenteral feeding experiment – different ways to supply TYR Phenylalanine O2 Phenylalanine Hydroxylase Tyrosine H2O PKU - Phenylketonuria Autosomal recessive genetic disorder - PAH Neonatal Genetic Screening Phenylalanine NO (PAH) Phenylalanine Hydroxylase Phenylketones In urine, toxic to developing brain Tyrosine Becomes indispensable Medical Nutrition Therapy Phenylketonuria • Non-functioning Phenylalanine Hydroxylase • PHE is not hydroxylated to TYR • PHE builds up and is metabolized by alternate pathway to Phenylketones • Damages the developing brain • Neonatal screening programs • Medical Nutrition Therapy needs to be diagnosed right after bc toxic critically important • Keep PHE and phenylketones low • TYR is an essential amino acid bc can’t be produced by phenylalanine SNPs (single nucleotide polymorphisms) and genetic disease (eg Sickle Cell Anemia) stuck in capillaires: painful Sickle-cell anaemia is marked by red blood cells that are misshapen and sticky, affecting blood flow.Credit: Eye Of Science/SPL single nucleotide substation in beta chain change conformation and ability to carry oxygen CRISPR-cas9 Gene Editing Therapy Casgevy Aim: to trigger production of Gammahaemoglobin that is normally made only in developing fetuses. Production of this fetal haemoglobin is typically shut off soon after birth by a gene called BCL11A. Therapy disables BCL11A, allowing fetal-haemoglobin production to resume. 2 alpha and 2 gamma: picks up oxygen from maternal blood supply After birth: stop producing gamma and produced beta Production of gamma so no sickle type harvest bone marrow and patient has chemotherapy (destroys stem cell) stem cells produced gamma in lab and put it in bone marrow of patient —> no more sickle cell https://www.nature.com/articles/d41586-023-03317-7?utm_source=Live+Audience&utm_campaign=583f650fad-briefing-dy20231030&utm_medium=email&utm_term=0_b27a691814-583f650fad-49174603 Cystic Fibrosis • Autosomal recessive • Poorly functioning chloride channel CFTR • Transmembrane conductance regulator protein (CFTR)is misfolded • Thick mucus in lungs…infections – difficult to fix sticky prone to lung infections • Pancreatic enzyme replacement…oral coated enzymes to facilitate digestion – easy to fix pills • Medical Nutrition Therapy – the cornerstone of treatment for growth and immune function • CFTR first human gene to be identified – Hospital for Sick Children in 1980’s cause problems • Now 2000 known polymorphisms that more SNIPS more severe than others • Lung transplant • Trikafta® – combination drug therapy helps totally effective for a good part of the genes variant • Stabilize the protein of protein • Increase migration to cell membrane • CRISPR? https://www.nature.com/articles/d41586-020-02106-w https://www.nature.com/articles/d41586-023-02890-1?utm_source=Live+Audience&utm_campaign=cb94bd1351-briefing-tr20230920&utm_medium=email&utm_term=0_b27a691814-cb94bd1351-49174603&mc_cid=cb94bd1351&mc_eid=8bc0b7dd7c Conditional Indispensability AA synthesis may be limited… patient, feeding regimen, function…. Intestine Kidney Glutamate, Proline Citrulline Citrulline Arginine ammonia comes from aa catabolism Ammonia detoxification Polyamine synthesis (blood Nitric oxide synthesis vessels ?) hyper metabolic adults and babies can’t make enough but normal adult yes When arginine is low, protein synthesis is not affected that much, but ammonia detoxification yes, urea cycle is disrupted = toxic to brain = seizures, possibly death Giving precursor (citrulline) helps —> endogenous synthesis Creatine synthesis in muscle Protein Synthesis Serine Glucose synthesized from 3C intermediate 3-phosphoglycerate Pyruvate Serine … but the story doesn’t end here! Cori Cycle pyruvate accepting amino group —> alanine going back to liver —> gluconeogenesis LIVER Gluco-neogenesis MUSCLE BLOOD Glycolysis 6 ATP 2 ATP 2 Pyruvate 2 Pyruvate anabolic 2 Lactate 2 Lactate 2 Lactate Serine tracers [U-13C]Glucose M+6 Glucose M+3 3-phosphoglycerate M+3 Pyruvate if serine were synthesized from metabolic glycolysis, Serine Hypothesis: should get M+3 Not that simple bc Cori Cycle M+3? Serine synthesis all that C exchange: M+ 3, M+2, M+1 If serine is produced through gluconeogenesis: M+1, M+2 If from glycolysis: M+3 Serine precursor can go into TCA cycle Pyruvate and lactate: only from glycolysis Serine synthesis AAs synthesized from intermediates of interorgan glucose metabolism AAs made from TCA cycle intermediates • Oxaloacetate  Aspartate • Aspartate  Asparagine • α-Ketoglutarate  Glutamate • Glutamate  Glutamine • Glutamate  Glutamate semialdehyde  proline AA Synthesis TA TA TA TA Creatine-P ATP Creatine ATP P Creatine Kinase ADP Resting muscle Creatine-P ADP Working muscle Creatine-P good reservoir of energy Muscle adaptations Energy reserve: Fuel reserve: creatine phosphate glycogen —> only for glycolysis Oxygen reserve: Purpose:? myoglobin: 1 alpha chain bc when exercising it, we need all of these things Special Functions of amino acids related to vitamins: Niacin • NAD(P) nicotinamide adenine dinucleotide function: • Synthesized from Niacin vitamin B3 • Niacin: diet + synthesized from TRP (requiring pyridoxine) • Review definition of essentiality • Deficiency: Pellagra: 4D’s – dermatitis, diarrhea, dementia, death • History and culture: • Has caused more deaths in the US than any other nutritient deficiency • Low protein diets with corn as the main protein source – low in TRP and niacin has very low bioavailability • Hominy is corn treated with alkali • Complementary proteins – corn (low in LYS and TRP, high in S AA’s) and beans (high in LYS and TRP, low in S AA’s) • Public Policy in Canada: Is Niacin deficiency a problem? Special Functions of amino acids related to energy metabolism Coenzyme A cofactor —> activator of molecules • Function: essential with carbonyl groups or as a carrier of acyl moieties • Synthesized from Pantothenic acid + cysteine + ATP (and required ATP energy) Coenzyme Q = ubiquinone phosphorylation process in mitochondria which • Function: oxidative converts the energy in carbohydrates and FA into ATP to drive cellular machinery and synthesis • Synthesized from PHE or TYR + Acetyl CoA Other special products • Tyrosine  thyroxine, epinephrine, norepinephrine, melanin • Tryptophan  serotonin • Glutamate and glutamine  fuel for intestinal cells, lymphocyte proliferation • Cysteine  taurine • ……..