Download Glycogen Storage Disease

Integration of Metabolism
FUELS, METABOLITES AND DISORDERS
FUELS
Starch, Glucose
Mannose
Sucrose (Fructose)
Amino Acids
Glycerol
Fat, Phospholipid
Fatty Acids
Sorbitol
Nucleic Acids(minor)
Lactose(Galactose)
Ketone Bodies
URINE
METABOLITES
1-3
BILE/FECES
METABOLITES
NH4,+ SO42-, HPO42Creatinine
Urea, Urate
17-Ketosteroids, -alanine
-Aminoisobutyrate
Ketone Bodies
Polyamines
Xanthurenic acid
Urobilinogen, Urobilin
Cholesterol,
Bile Acids
Bilirubin
Stercobilin
Lipid
(Steatorrhea)
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
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)
1-3
Metabolic Disturbances and Fuel Intolerances
Carbohydrate Intolerance
Protein Intolerance
Diabetes mellitus
Fructose Intolerance
Cushing's Disease (ACTH)
Galactosemia
Lactose Intolerance
Methylmalonyl aciduria
Maple Syrup urine disease
Vitamin B12/Biotin deficiency
Urea cycle deficiency
Phenylketonuria
Lipid Intolerance
LPL Def. (VLDL or Chylo )
MCAD
1- 4
Exercise Intolerance:
(Early vs. Prolonged)
Ketoacidosis/Ketonemia
Decreased PFK-1
McArdles' disease
Carnitine, CAT1 deficiency
MCAD deficiency
Diabetic ketoacidosis
Organic acidurias
Alcoholic ketoacidosis
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)
mild hypoglycemia
- Cori’s
Glycogen Phosphorylase
- McArdle’s
no hypoglycemia - low lactate upon exercise
Glycogen Synthase - hypoglycemia / hyperketonemia
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:
Gluconeogenesis:
Glycogenolysis:
Glycogenesis:
Fatty acid Synth:
Beta Oxidation :
Cholesterol Synth:
Pyrimidine Synth:
Purine Synthesis :
Heme Synthesis:
Ammoniagenesis:
Citric Acid Cycle
Urea Cycle
Hexokinase, Phosphofructokinase-1,
Pyruvate kinase (ATP, Ala)
Pyruvate carboxylase,
Fructose 1,6-bisphosphatase
Glycogen phosphorylase kinase ( Ca2+ )
Glycogen phosphorylase
(AMP, ATP, Glucose)
Glycogen Synthase (Glucose 6-P)
Acetyl CoA carboxylase
CAT I (Malonyl CoA), Thiolase (Acetyl CoA)
-hydroxy fatty acyl CoA dehyd. (NADH)
HMGCoA reductase (Cholesterol)
Carbamyl Pi Synthetase II (UTP)
PRPP amidotransferase (Nucleotides)
-Aminolevulinic acid synthase (Heme)
Glutamate Dehydrogenase (ADP/GDP)
Citrate Synthase, IC and  KG Dehyd.
(NADH, ATP)
Carbamyl Pi Synthetase I (N-Acetyl Glu)
1-4
Covalent Modification (Response of Activity to
Phosphorylation, (Acute or Fine Control)
Glycogen phosphorylase ()
Glycogen synthase ()
Hepatic pyruvate kinase ()
Pyruvate dehydrogenase ()
Adipose triacylglycerol lipase ()
Acetyl CoA carboxylase ()
HMG CoA reductase ()
Phosphorylase b kinase ()
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)
1-5
A
D
B
Glucose 6-Pi
C
UDPGlucouronate
E
Bilirubin
Diglucuronide
A - Glycogen Storage
Disease - Type I
C - McArdles’ or
Cori’s Disease
B - Glucose 6-Pi Dehydrogenase
Deficiency
D - Galactosemia
E - Crigler-Najjar Syndrome (bilirubin glucuronyltransferase)
1-5/6
A - Glycogen Storage Disease (Type I):
Both GNG and Glycogenolysis 
HallMarks:
Excess Glycogen Accumulation
Hypertriglyceridemia
Fasting Hypoglycemia
Hyperuricemia
B - Glucose 6-Pi Dehyd. Def. - Acute Hemolytic Anemia:
Stress --> Red Cell [NADPH] 
H2O2 and Lipid Peroxides 
MetHb 
Hematocrit 
Haptoglobulin 
Bilrubin/BDG 
Hemolysis 
Glycogen Storage
Disease Type I
Blood Glucose 
Feed-Fast Cycles
Glucose 6-Phosphate 
Glycogen 
PRPP 
Adipose
Fatty Acids
+ Glycerol
DHAP +
Acetyl CoA 
VLDL 
Lactate 
Purines 
RBC
1-6
DHAP
DHAP
Homocysteine
Pyruvate
A
OAA
Asp
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
Acetyl CoA
Acetyl CoA
1-7
B
C
+
Ketoacidosis
(DKA)
A - Starvation
B - Diabetes (IDDM, Type I)
C - Carnitine/CAT I Def.
Lipolysis > ketone body utilization
Hypoketonemia
PRPP
1-8
C
A
PRPP
A - Hyperuricemia/Gout ( HGPRT  )
(Lesch-Nyhan Syndrome)
B
C - Hyperuricemia - urate
underexcretion (renal failure,
lactic acidosis, alcoholism)
B - Hypoxia or Phosphate Trapping
O2   Oxid. Phosp. & ATP  )
Pi   Oxid. Phosp., Glycolysis, Glycogenolysis 
Phosphate Trapping: Fructose Intolerance, Galactosemia,
Von Gierke’s Glycogen Storage
1-8
Orotic Aciduria - Poor growth, megaloblastic anemia unresponsive to folate / B12
OROTATE
PRPP
A
A’
A - Orotate Phosphoribosyl transferase
A’ - OMP Decarboxylase
Treatment: feed uridine or cytidine
UMP
Synthase
1-9
Dietary Biotin
The
Biotin
Cycle
1-9
• Only Four Enzymes in Humans Require Biotin:
Pyruvate
Propionyl CoA
Acetyl CoA
Methyl crotonyl CoA
Carboxylase (mito.)
Carboxylase “
Carboxylase (cyto.)
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 
Mito. CoA Depletion or inhibition
Secondary Carnitine
deficiency, -oxidation 
Glycine Cleavage
Enzyme 
N-acetyl Glu
Synthase 
N-Acetyl Glu 
Energy 
Gly 
NH3 
Other Organoacidurias: Maple syrup urine, methylmalonic
aciduria and HMGCoA lyase defect act similarly
1-11
Atypical PKU - Biopterin Reductase Deficiency
Phenylacetate
Phenyllactate
Phenylpyruvate
B - Albinism
Parkinson Disease
5 HO-indole
acetic acid
Melatonin
Features: Mental retardation despite
Phe restriction ; give
tetrahydrobiopterin
(won’t cross blood brain barrier) - give
L-DOPA and 5-HO-Trp
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
GLYCOLYSIS 1
1-12
B
Pentoses
C
*
B
A
A - Heriditary Fructose
Intolerance (HFI)
B - GNG Deficiency: Lactic
Acidosis / Hypoglycemia
C - Galactosemia
1-13
GLYCOLYSIS 2
PKA, ATP
A
A - Hemolytic Anemia - PK deficiency(C.C. 7.8)
Pyruvate Dehydrogenase
E3 Deficiency:
lactic acid,  KG and
-ketoacids(bcaa) 
1-14
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
1-15
Muscle Uptake, Growth
Fasting - Hepatic -Low Glucose
Ala,
PKA
Ketone
Bodies
Urea 
GNG Energy
from -oxidation
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
High Protein Diet
Glucocorticoids
Glucagon
Insulin
Glucagon
Glucocorticoids
Insulin
Carbohydrate
Feeding
Low fat diet
High Carbohydrate
Glucagon
Insulin,
Loss of Bile acids,
Dietary Cholest. 
Insulin
Glucagon
Epinephrine
Growth and develop.
Insulin
Glycolysis
Gluconeogenesis
Pentose Pathway
Lipogenesis
Lipolysis
Cholesterol Biosynthesis
Glycogenesis
Glyogenolysis
Glucagon
Insulin
Starvation
Starvation
Insulin
Glucagon
Starvation,
Dietary Cholest.
Glucagon
Insulin
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