Integration of MetabolismIntegration of Metabolism
FUELS, METABOLITES AND DISORDERS
FUELS URINE BILE/FECES METABOLITES
METABOLITES
Starch, Glucose NH4,+ SO42-, HPO4
2- Cholesterol,Mannose Creatinine Bile Acids Sucrose (Fructose) Urea, Urate Bilirubin Amino Acids 17-Ketosteroids, -alanine StercobilinGlycerol -Aminoisobutyrate Lipid Fat, Phospholipid (Steatorrhea)Fatty Acids Ketone BodiesSorbitol PolyaminesNucleic Acids(minor) Xanthurenic acidLactose(Galactose) Urobilinogen, UrobilinKetone Bodies
FUELS, METABOLITES AND DISORDERS
FUELS URINE BILE/FECES METABOLITES
METABOLITES
Starch, Glucose NH4,+ SO42-, HPO4
2- Cholesterol,Mannose Creatinine Bile Acids Sucrose (Fructose) Urea, Urate Bilirubin Amino Acids 17-Ketosteroids, -alanine StercobilinGlycerol -Aminoisobutyrate Lipid Fat, Phospholipid (Steatorrhea)Fatty Acids Ketone BodiesSorbitol PolyaminesNucleic Acids(minor) Xanthurenic acidLactose(Galactose) Urobilinogen, UrobilinKetone 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
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
1-3
Exercise Intolerance: Ketoacidosis/Ketonemia(Early vs. Prolonged)
Decreased PFK-1 Diabetic ketoacidosisMcArdles' disease Organic acidurias Carnitine, CAT1 deficiency Alcoholic ketoacidosisMCAD deficiency Glycogen storage disease
1- 4
Glycogen Storage:
Glucose 6-phosphatase (Type 1) - Von Gierke’smild to severe hypoglycemia - only GNG tissues affected
Lysosomal -glucosidase (Type 2) - Pompe’sno hypoglycemia --> fatal - all tissues affected
Amylo-1,6-glucosidase (Type 3) - Cori’smild hypoglycemia
Glycogen Phosphorylase - McArdle’sno hypoglycemia - low lactate upon exercise
Glycogen Synthase - hypoglycemia / hyperketonemia
Screening and Treatment of Metabolic Disease
Disease Screening Programs Methods of Treatment
Sickle Cell Disease * Dietary and Vitamin Therapy Tyrosinemia I Drug, hormone or metabolitePhenylketonuria * 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
1-4
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 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
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)
1-51-5
A
A - Glycogen Storage Disease - Type I
B
B - Glucose 6-Pi Dehydrogenase
Deficiency
C
C - McArdles’ or Cori’s Disease
D
D - Galactosemia
1-5
UDP-Glucouronate
BilirubinDiglucuronide
E - Crigler-Najjar Syndrome (bilirubin glucuronyltransferase)
E
Glucose 6-PiGlucose 6-Pi
A - Glycogen Storage Disease (Type I):
Both GNG and Glycogenolysis HallMarks:
Excess Glycogen AccumulationHypertriglyceridemiaFasting HypoglycemiaHyperuricemia
B - Glucose 6-Pi Dehyd. Def. - Acute Hemolytic Anemia:
Stress --> Red Cell [NADPH] H2O2 and Lipid Peroxides MetHb Hemolysis Hematocrit Haptoglobulin Bilrubin/BDG
1-5/6
Glycogen
Glucose 6-Phosphate Feed-Fast Cycles
DHAP +Acetyl CoA
VLDL
Lactate
RBC
Adipose
Fatty Acids + Glycerol
Blood Glucose
PRPP
Purines
Glycogen StorageDisease Type I
A - Homocystinuria, B6 responsive
Cytosolic NADH Utilization: Mitochondrial and Citrate Shuttles Pyruvate --> Lactate Glycerol 3-Pi Synthesis for TAG A.A. Metab.: Ser -->--> 3-Phosphoglycerate
1-6
APyruvate
OAA
Asp
Homocysteine
DHAPDHAPDHAP
B - Diabetes (IDDM, Type I) Lipolysis > ketone body utilization
A - StarvationC - Carnitine/CAT I Def. Hypoketonemia
- 1-7Acetyl CoAB
-
Ketoacidosis (DKA)
+
C
Acetyl CoAAcetyl CoA
A - Hyperuricemia/Gout ( HGPRT ) (Lesch-Nyhan Syndrome)
A
B - Hypoxia or Phosphate Trapping O2 Oxid. Phosp. & ATP ) Pi Oxid. Phosp., Glycolysis, Glycogenolysis
B
C - Hyperuricemia - urate underexcretion (renal failure, lactic acidosis, alcoholism)
C
PRPP 1-8
PRPPPRPP
A’
A
A - Orotate Phosphoribosyl transferase A’ - OMP Decarboxylase
Treatment: feed uridine or cytidine
Phosphate Trapping: Fructose Intolerance, Galactosemia, Von Gierke’s Glycogen Storage
Orotic Aciduria - Poor growth, megaloblastic anemia - unresponsive to folate / B12
1-8
UMPSynthase
PRPPPRPPOROTATE
1-9
TheBiotinCycle
TheBiotinCycle
Dietary BiotinDietary Biotin
• 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)
1-9
Oral biotinsupplementoften effective
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 B12 deficiency ,
homocysteine may also rise
1-10
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
PhenylacetatePhenyllactatePhenylpyruvate
5 HO-indoleacetic acid
Features: Mental retardation despitePhe restriction ; give tetrahydrobiopterin (won’t cross blood brain barrier) - giveL-DOPA and 5-HO-Trp
Melatonin
1-11
B - Albinism
Parkinson Disease
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
A - Heriditary Fructose Intolerance (HFI)
B - GNG Deficiency: Lactic Acidosis / Hypoglycemia
C - Galactosemia
GLYCOLYSIS 1
A
B
B
C
1-12
Pentoses
*
A
A - Hemolytic Anemia - PK deficiency(C.C. 7.8)
1-13GLYCOLYSIS 2
PKA, ATP
Pyruvate Dehydrogenase
Five Coenzymes: NAD+, Thiamin, Pantothenic acid, lipoic acid, FAD
Five Enzymes: PDH (E1), Lipoyl dehyd. (E2), and transacetylase (E3)
kinase and phosphatase
1-14E3 Deficiency:lactic acid, KG and -ketoacids(bcaa)
Feasting - Hepatic- High Glucose
Muscle Uptake, Growth
1-15
Fasting - Hepatic -Low Glucose
KetoneBodies
Ala,PKA
GNG Energyfrom -oxidation
Urea
Mevinolin, Lipotor - “statins”- lower plasma cholesterol 20-60 %
A
A - Smith-Lemli-Opitz (SLO) syndrome - 7-DHC reductase deficiency - birth defects
1-18
[C30]
[C30]
METABOLISM INCREASE DECREASE
Amino acid degradation Starvation Growth and develop.High Protein Diet InsulinGlucocorticoidsGlucagon
Glycolysis Insulin GlucagonGluconeogenesis Glucagon
Glucocorticoids InsulinPentose Pathway Insulin Starvation
CarbohydrateFeeding
Lipogenesis Low fat dietHigh Carbohydrate Starvation
Lipolysis Glucagon InsulinCholesterol Biosynthesis Insulin, Glucagon
Loss of Bile acids, Starvation, Dietary Cholest. Dietary Cholest.
Glycogenesis Insulin GlucagonGlyogenolysis 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