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Integration of Metabolism. FUELS, METABOLITES AND DISORDERS FUELS URINE BILE/FECES METABOLITES METABOLITES Starch, Glucose NH 4, + SO 4 2-, HPO 4 2- Cholesterol,

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Presentation on theme: "Integration of Metabolism. FUELS, METABOLITES AND DISORDERS FUELS URINE BILE/FECES METABOLITES METABOLITES Starch, Glucose NH 4, + SO 4 2-, HPO 4 2- Cholesterol,"— Presentation transcript:

1 Integration of Metabolism

2 FUELS, METABOLITES AND DISORDERS FUELS URINE BILE/FECES METABOLITES METABOLITES Starch, Glucose NH 4, + SO 4 2-, HPO 4 2- Cholesterol, Mannose Creatinine Bile Acids Sucrose (Fructose) Urea, Urate Bilirubin Amino Acids 17-Ketosteroids, -alanine Stercobilin Glycerol -Aminoisobutyrate Lipid Fat, Phospholipid (Steatorrhea) Fatty Acids Ketone Bodies Sorbitol Polyamines Nucleic Acids(minor) Xanthurenic acid Lactose(Galactose) Urobilinogen, Urobilin Ketone Bodies FUELS, METABOLITES AND DISORDERS FUELS URINE BILE/FECES METABOLITES METABOLITES Starch, Glucose NH 4, + SO 4 2-, HPO 4 2- Cholesterol, Mannose Creatinine Bile Acids Sucrose (Fructose) Urea, Urate Bilirubin Amino Acids 17-Ketosteroids, -alanine Stercobilin Glycerol -Aminoisobutyrate Lipid Fat, Phospholipid (Steatorrhea) Fatty Acids Ketone Bodies Sorbitol Polyamines Nucleic Acids(minor) Xanthurenic acid Lactose(Galactose) Urobilinogen, Urobilin Ketone Bodies 1-3

3 Metabolic Diseases and Metabolites Biotin deficiency: propionic acid, branched -ketoacids Amino Acids -->--> Propionic Acid ----> Succinyl CoA B 12 deficiency: methylmalonate, homocysteine Hemolytic anemia and certain porphyrias: bilirubin PKU: Phe, phenyllactate, phenylacetate, phenylpyruvate Hypoxia: lactic acid Hyperammonemia: citrulline, argininosuccinate, etc. Biopterin or biopterin reductase deficiency: decrease in 5-hydroxy-indoleacetic, vanillyl mandelic acid, homovanillic acids 1-3

4 Metabolic Diseases and Metabolites (continued) Folic acid deficiency: formiminoglutamic acid (FIGLU) Diabetes mellitus: glucose (blood and urine), HbA 1c, DKA Fructose intolerance: fructose or fructose 1-P i *Cystinuria with basic A.A. renal transporter defect: cystine *Hartnup's disease: neutral aminoaciduria (Trp loss -> Niacin ) Homocystinuria: homocysteine Gaucher's disease: glucocerebrosides (lysosomal disorder)

5 Metabolic Disturbances and Fuel Intolerances Carbohydrate Intolerance Protein Intolerance Diabetes mellitus Methylmalonyl aciduria Fructose Intolerance Maple Syrup urine disease Cushing's Disease (ACTH ) Vitamin B 12 /Biotin deficiency Galactosemia Urea cycle deficiency Lactose Intolerance Phenylketonuria Lipid Intolerance LPL Def. (VLDL or Chylo ) MCAD 1-3

6 Exercise Intolerance: Ketoacidosis/Ketonemia (Early vs. Prolonged) Decreased PFK-1 Diabetic ketoacidosis McArdles' disease Organic acidurias Carnitine, CAT1 deficiency Alcoholic ketoacidosis MCAD deficiency Glycogen storage disease 1- 4

7 Glycogen Storage: Glucose 6-phosphatase (Type 1) - Von Gierkes mild to severe hypoglycemia - only GNG tissues affected Lysosomal -glucosidase (Type 2) -Pompes no hypoglycemia -->fatal - all tissues affected Amylo-1,6-glucosidase (Type 3) -Coris mild hypoglycemia Glycogen Phosphorylase -McArdles no hypoglycemia - low lactate upon exercise Glycogen Synthase - hypoglycemia / hyperketonemia

8 Screening and Treatment of Metabolic Disease Disease Screening ProgramsMethods of Treatment Sickle Cell Disease * Dietary and Vitamin Therapy Tyrosinemia IDrug, hormone or metabolite Phenylketonuria * administration (allopurinol, Galactosemia * benzoic or phenylacetic acid, Homocystinuria insulin, carnitine, heme, etc.) Biotinidase DeficiencyEnzyme replacement Maple syrup urine diseaseGenetic engineering (stem cell Adrenal hyperplasia replacement) Hypothyroidism (Cretinism) *Organ transplantation 1-4

9 Allosteric Regulation Glycolysis: Hexokinase, Phosphofructokinase-1, Pyruvate kinase (ATP, Ala) Gluconeogenesis: Pyruvate carboxylase, Fructose 1,6-bisphosphatase Glycogenolysis: Glycogen phosphorylase kinase ( Ca 2+ ) Glycogen phosphorylase (AMP, ATP, Glucose) Glycogenesis: Glycogen Synthase (Glucose 6-P) Fatty acid Synth: Acetyl CoA carboxylase Beta Oxidation : CAT I (Malonyl CoA), Thiolase (Acetyl CoA) -hydroxy fatty acyl CoA dehyd. (NADH) Cholesterol Synth: HMGCoA reductase (Cholesterol) Pyrimidine Synth: Carbamyl P i Synthetase II (UTP) Purine Synthesis : PRPP amidotransferase (Nucleotides) Heme Synthesis: -Aminolevulinic acid synthase (Heme) Ammoniagenesis:Glutamate Dehydrogenase (ADP/GDP) Citric Acid CycleCitrate Synthase, IC and KG Dehyd. (NADH, ATP) Urea CycleCarbamyl Pi Synthetase I (N-Acetyl Glu)

10 Covalent Modification (Response of Activity to Phosphorylation, (Acute or Fine Control) Glycogen phosphorylase ( ) Adipose triacylglycerol lipase ( ) Glycogen synthase ( ) Acetyl CoA carboxylase ( ) Hepatic pyruvate kinase ( ) HMG CoA reductase ( ) Pyruvate dehydrogenase ( ) Phosphorylase b kinase ( ) 1-4

11 Compartmentation Cytosolic: Glycolysis, pentose pathway, fatty acid / triacylglycerol synthesis, nucleotide synthesis, cholesterol biosynthesis Mitochondrial: TCA, electron transport, oxidation of fatty acids, ketone body formation, pyruvate dehyd. Interplay: Urea synthesis; gluconeogenesis; fatty acid synthesis, steroid biosynthesis and heme biosynthesis Shuttles: Malate/aspartate, DHAP/glycerol phosphate (electrons), citrate (acetyl CoA), carnitine (F.A.s) Compartmentation Cytosolic: Glycolysis, pentose pathway, fatty acid / triacylglycerol synthesis, nucleotide synthesis, cholesterol biosynthesis Mitochondrial: TCA, electron transport, oxidation of fatty acids, ketone body formation, pyruvate dehyd. Interplay: Urea synthesis; gluconeogenesis; fatty acid synthesis, steroid biosynthesis and heme biosynthesis Shuttles: Malate/aspartate, DHAP/glycerol phosphate (electrons), citrate (acetyl CoA), carnitine (F.A.s) 1-5

12 A A - Glycogen Storage Disease - Type I B B - Glucose 6-Pi Dehydrogenase Deficiency C C - McArdles or Coris Disease D D - Galactosemia 1-5 UDP- Glucouronate Bilirubin Diglucuronide E - Crigler-Najjar Syndrome (bilirubin glucuronyltransferase) E Glucose 6-P i

13 A - Glycogen Storage Disease (Type I): Both GNG and Glycogenolysis HallMarks: Excess Glycogen Accumulation Hypertriglyceridemia Fasting Hypoglycemia Hyperuricemia B - Glucose 6-P i Dehyd. Def. - Acute Hemolytic Anemia: Stress --> Red Cell [NADPH] H 2 O 2 and Lipid Peroxides MetHb Hemolysis Hematocrit Haptoglobulin Bilrubin/BDG 1-5/6

14 Glycogen Glucose 6-Phosphate Feed-Fast Cycles DHAP + Acetyl CoA VLDL Lactate RBC Adipose Fatty Acids + Glycerol Blood Glucose PRPP Purines Glycogen Storage Disease Type I

15 A - Homocystinuria, B 6 responsive Cytosolic NADH Utilization: Mitochondrial and Citrate Shuttles Pyruvate --> Lactate Glycerol 3-Pi Synthesis for TAG A.A. Metab.: Ser -->--> 3-Phosphoglycerate 1-6 A Pyruvate OAA Asp Homocysteine DHAP

16 B - Diabetes (IDDM, Type I) Lipolysis > ketone body utilization A - Starvation C - Carnitine/CAT I Def. Hypoketonemia - 1-7Acetyl CoA B - Ketoacidosis (DKA) + C Acetyl CoA

17 A - Hyperuricemia/Gout ( HGPRT ) (Lesch-Nyhan Syndrome) A B - Hypoxia or Phosphate Trapping O 2 Oxid. Phosp. & ATP ) P i Oxid. Phosp., Glycolysis, Glycogenolysis B C - Hyperuricemia - urate underexcretion (renal failure, lactic acidosis, alcoholism) C PRPP 1-8 PRPP

18 A A A - Orotate Phosphoribosyl transferase A - OMP Decarboxylase Treatment: feed uridine or cytidine Phosphate Trapping: Fructose Intolerance, Galactosemia, Von Gierkes Glycogen Storage Orotic Aciduria - Poor growth, megaloblastic anemia - unresponsive to folate / B UMP Synthase PRPP OROTATE

19 1-9 The Biotin Cycle The Biotin Cycle Dietary Biotin

20 Only Four Enzymes in Humans Require Biotin: Pyruvate Carboxylase (mito.) Propionyl CoA Carboxylase Acetyl CoA Carboxylase (cyto.) Methyl crotonyl CoA Carboxylase (Leu catabolism) Many other carboxylases dont require biotin: Malic enzyme, PEPCK, Carbamoyl Pi Synthetases, etc. Biotin/Biotin-like Deficiency: Biotinidase Deficiency Holocarboxylase Deficiency Raw egg ingestion (avidin) 1-9 Oral biotin supplement often effective

21 Multiple Carboxylase Deficiency (Organoaciduria) Ketoacidosis - ketoacid of amino acids, anion gap Hypoglycemia and Lactic acidosis - pyruvate carboxylase Dermatitus - fatty acids synthesis - acetyl CoA carboxylase Hyperglycinemia - glycine cleavage enzyme and glycine Hyperammonemia but pH low - N-acetyl Glu synthase, urea cycle Methylmalonyl aciduria: enzyme or B 12 deficiency, homocysteine may also rise 1-10

22 Summary of Multiple Carboxylase Deficiency Mitochondrial propionic acid, branched chain ketoacids and their CoA derivatives Secondary Carnitine deficiency, -oxidation Energy Glycine Cleavage Enzyme N-acetyl Glu Synthase Gly N-Acetyl Glu Mito. CoA Depletion or inhibition Other Organoacidurias: Maple syrup urine, methylmalonic aciduria and HMGCoA lyase defect act similarly NH 3

23 Atypical PKU - Biopterin Reductase Deficiency Phenylacetate Phenyllactate Phenylpyruvate 5 HO-indole acetic acid Features: Mental retardation despite Phe restriction ; give tetrahydrobiopterin (wont cross blood brain barrier) - give L-DOPA and 5-HO-Trp Melatonin 1-11 B - Albinism Parkinson Disease

24 Other PKUs: Classical : (> 95 % of PKUs) Most common inborn error - only degradative pathway involved - restrict Phe to avoid post-natal mental retardation Maternal :Mother is -/+ or -/- for PKU - avoid aspartame (aspartylphenylalanine methyl ester) Serotonin: (CNS) - Neurotransmitter; (Platelet) - vasoconstrictor; (GI) - enterochromaffin cells (tumors) Pheochromocytoma: Cancer of the adrenal medulla. Overproduction of epinephrine - vanillylmandelic high in urine - hypertension

25 A - Heriditary Fructose Intolerance (HFI) B - GNG Deficiency: Lactic Acidosis / Hypoglycemia C - Galactosemia GLYCOLYSIS 1 A B B C 1-12 Pentoses *

26 A A - Hemolytic Anemia - PK deficiency(C.C. 7.8) 1-13 GLYCOLYSIS 2 PKA, ATP

27 Pyruvate Dehydrogenase Five Coenzymes: NAD +, Thiamin, Pantothenic acid, lipoic acid, FAD Five Enzymes: PDH (E 1 ), Lipoyl dehyd. (E 2 ), and transacetylase (E 3 ) kinase and phosphatase 1-14 E3 Deficiency: lactic acid, KG and -ketoacids(bcaa)

28 Feasting - Hepatic- High Glucose Muscle Uptake, Growth 1-15

29 Fasting - Hepatic -Low Glucose Ketone Bodies Ala, PKA GNG Energy from -oxidation Urea

30 Mevinolin, Lipotor - statins- lower plasma cholesterol % A A - Smith-Lemli-Opitz (SLO) syndrome - 7-DHC reductase deficiency - birth defects 1-18 [C30]

31 METABOLISMINCREASE DECREASE Amino acid degradationStarvation Growth and develop. High Protein Diet Insulin Glucocorticoids Glucagon GlycolysisInsulin Glucagon GluconeogenesisGlucagon Glucocorticoids Insulin Pentose PathwayInsulin Starvation Carbohydrate Feeding LipogenesisLow fat diet High Carbohydrate Starvation LipolysisGlucagonInsulin Cholesterol BiosynthesisInsulin, Glucagon Loss of Bile acids, Starvation, Dietary Cholest. Dietary Cholest. GlycogenesisInsulinGlucagon GlyogenolysisGlucagonInsulin Epinephrine

32 Metabolic Entry Points of Amino Acids Pyruvate: Trp, Thr, Gly, Ala, Cys, Ser Acetyl CoA/Acetoacetyl CoA (no net carbohyd.synthesis): Ile, Trp, Phe, Leu, Tyr, Lys -Ketoglutarate:Glu, Gln, His, Pro, Arg, Orn Succinyl CoA:Met, Thr, Val, Ile Oxaloacetic Acid:Asp, Asn Fumarate: Asp (urea cycle), Phe, Tyr


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