1. Integration of Metabolism

2. FUELS, METABOLITES AND DISORDERS FUELS URINE BILE/FECES
METABOLITES METABOLITES
Starch, Glucose NH4,+ SO42-, HPO Cholesterol,
Mannose Creatinine Bile Acids
Sucrose (Fructose) Urea, Urate Bilirubin
Amino Acids 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
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

4. 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)

5. 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

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

7. 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

8. 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

9. 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)

10. 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 ()

11. 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)

12. 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

13. 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 

14. 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 

15. 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

16. - 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

17. 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)

18. 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

19. 1-9
Dietary Biotin
The
Biotin
Cycle

20. 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

21. 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 

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
NH3 

23. 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

24. 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

25. 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

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

27. 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

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

31. 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

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