Integration of Metabolism

FUELS, METABOLITES AND DISORDERS FUELS URINE BILE/FECES METABOLITES METABOLITES Starch, Glucose NH4,+ SO42-, HPO42- 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

Metabolic Diseases and Metabolites Biotin deficiency: propionic acid, branched -ketoacids Amino Acids -->--> Propionic Acid ----> Succinyl CoA B12 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

Metabolic Diseases and Metabolites (continued) Folic acid deficiency: formiminoglutamic acid (FIGLU) Diabetes mellitus: glucose (blood and urine), HbA1c, DKA Fructose intolerance: fructose or fructose 1-Pi *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)

Metabolic Disturbances and Fuel Intolerances 1-3 Metabolic Disturbances and Fuel Intolerances Carbohydrate Intolerance Protein Intolerance Diabetes mellitus Methylmalonyl aciduria Fructose Intolerance Maple Syrup urine disease Cushing's Disease (ACTH) Vitamin B12/Biotin deficiency Galactosemia Urea cycle deficiency Lactose Intolerance Phenylketonuria Lipid Intolerance LPL Def. (VLDL or Chylo ) MCAD

Exercise Intolerance: Ketoacidosis/Ketonemia (Early vs. Prolonged) 1- 4 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

Glycogen Storage: Glucose 6-phosphatase (Type 1) - Von Gierke’s mild to severe hypoglycemia - only GNG tissues affected Lysosomal -glucosidase (Type 2) - Pompe’s no hypoglycemia --> fatal - all tissues affected Amylo-1,6-glucosidase (Type 3) - Cori’s mild hypoglycemia Glycogen Phosphorylase - McArdle’s no hypoglycemia - low lactate upon exercise Glycogen Synthase - hypoglycemia / hyperketonemia

Screening and Treatment of Metabolic Disease 1-4 Screening and Treatment of Metabolic Disease Disease Screening Programs Methods of Treatment Sickle Cell Disease * Dietary and Vitamin Therapy Tyrosinemia I Drug, hormone or metabolite Phenylketonuria * administration (allopurinol, Galactosemia * benzoic or phenylacetic acid, Homocystinuria insulin, carnitine, heme, etc.) Biotinidase Deficiency Enzyme replacement Maple syrup urine disease Genetic engineering (stem cell Adrenal hyperplasia replacement) Hypothyroidism (Cretinism) * Organ transplantation

Allosteric Regulation Glycolysis: Hexokinase, Phosphofructokinase-1, Pyruvate kinase (ATP, Ala) Gluconeogenesis: Pyruvate carboxylase, Fructose 1,6-bisphosphatase Glycogenolysis: Glycogen phosphorylase kinase ( Ca2+ ) 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 Pi Synthetase II (UTP) Purine Synthesis : PRPP amidotransferase (Nucleotides) Heme Synthesis: -Aminolevulinic acid synthase (Heme) Ammoniagenesis: Glutamate Dehydrogenase (ADP/GDP) Citric Acid Cycle Citrate Synthase, IC and  KG Dehyd. (NADH, ATP) Urea Cycle Carbamyl Pi Synthetase I (N-Acetyl Glu)

Covalent Modification (Response of Activity to 1-4 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 ()

Cytosolic: Glycolysis, pentose pathway, fatty acid / 1-5 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)

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

A - Glycogen Storage Disease (Type I): Both GNG and Glycogenolysis  HallMarks: Excess Glycogen Accumulation Hypertriglyceridemia Fasting Hypoglycemia Hyperuricemia 1-5/6 B - Glucose 6-Pi Dehyd. Def. - Acute Hemolytic Anemia: Stress --> Red Cell [NADPH]  H2O2 and Lipid Peroxides  MetHb  Hemolysis  Hematocrit  Haptoglobulin  Bilrubin/BDG 

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

DHAP A 1-6 Cytosolic NADH Utilization: Pyruvate OAA Asp Homocysteine DHAP DHAP Cytosolic NADH Utilization: Mitochondrial and Citrate Shuttles Pyruvate --> Lactate Glycerol 3-Pi Synthesis for TAG A.A. Metab.: Ser -->--> 3-Phosphoglycerate A - Homocystinuria, B6 responsive

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

PRPP C A B 1-8 PRPP A - Hyperuricemia/Gout ( HGPRT  ) C - Hyperuricemia - urate underexcretion (renal failure, lactic acidosis, alcoholism) C A PRPP B - Hypoxia or Phosphate Trapping O2   Oxid. Phosp. & ATP  ) Pi   Oxid. Phosp., Glycolysis, Glycogenolysis  B A - Hyperuricemia/Gout ( HGPRT  ) (Lesch-Nyhan Syndrome)

Phosphate Trapping: Fructose Intolerance, Galactosemia, Von Gierke’s Glycogen Storage 1-8 Orotic Aciduria - Poor growth, megaloblastic anemia - unresponsive to folate / B12 PRPP OROTATE A A’ A - Orotate Phosphoribosyl transferase A’ - OMP Decarboxylase Treatment: feed uridine or cytidine UMP Synthase

1-9 Dietary Biotin The Biotin Cycle

Pyruvate Carboxylase (mito.) Propionyl CoA Carboxylase “ 1-9 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 don’t require biotin: Malic enzyme, PEPCK, Carbamoyl Pi Synthetases, etc. Biotin/Biotin-like Deficiency: Biotinidase Deficiency Holocarboxylase Deficiency Raw egg ingestion (avidin) Oral biotin supplement often effective

Multiple Carboxylase Deficiency (Organoaciduria) 1-10 Methylmalonyl aciduria: enzyme or B12 deficiency , homocysteine may also rise 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 

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 NH3 

Atypical PKU - Biopterin Reductase Deficiency 1-11 Atypical PKU - Biopterin Reductase Deficiency Phenylacetate Phenyllactate Phenylpyruvate B - Albinism Parkinson Disease 5 HO-indole acetic acid Features: Mental retardation despite Phe restriction ; give tetrahydrobiopterin (won’t cross blood brain barrier) - give L-DOPA and 5-HO-Trp Melatonin

Other PKUs: Classical : (> 95 % of PKU’s) 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

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

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

Pyruvate Dehydrogenase 1-14 E3 Deficiency: lactic acid,  KG and -ketoacids(bcaa)  Five Coenzymes: NAD+, Thiamin, Pantothenic acid, lipoic acid, FAD Five Enzymes: PDH (E1), Lipoyl dehyd. (E2), and transacetylase (E3) kinase and phosphatase

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

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

A Mevinolin, Lipotor - “statins”- lower plasma cholesterol 20-60 % 1-18 Mevinolin, Lipotor - “statins”- lower plasma cholesterol 20-60 % [C30] [C30] A A - Smith-Lemli-Opitz (SLO) syndrome - 7-DHC reductase deficiency - birth defects

METABOLISM INCREASE DECREASE Amino acid degradation Starvation Growth and develop. High Protein Diet Insulin Glucocorticoids Glucagon Glycolysis Insulin Glucagon Gluconeogenesis Glucagon Glucocorticoids Insulin Pentose Pathway Insulin Starvation Carbohydrate Feeding Lipogenesis Low fat diet High Carbohydrate Starvation Lipolysis Glucagon Insulin Cholesterol Biosynthesis Insulin, Glucagon Loss of Bile acids, Starvation, Dietary Cholest.  Dietary Cholest. Glycogenesis Insulin Glucagon Glyogenolysis Glucagon Insulin Epinephrine

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