1. SSB End of Unit Review
Eric Niederhoffer
SIU-SOM

2. Submitted Questions
Which enzymes are inhibited by elevated NADH versus which steps cause elevated NADH?
Inhibited: Dehydrogenases
Elevated: ADH, AlDH
Specific inhibitory/activating substrate interactions with PFK1, PFK2
Inhibitory: ATP, citrate
Activating: F6P, F26BP, F16BP, NH4+, AMP, Pi
Why F16BP stimulates both PFK1 and PK?
Feed-forward activation
Significant and differentiating characteristics of metabolic diseases (examples given in RS)
Physical symptoms, metabolites

3. Cellular Processing Oh my! Now what? EtOH CAT MEOS ADH P450
Peroxisome
Cytosol ER
CAT
H2O2
H2O
ADH
NAD+
NADH
MEOS
NADP+
NADPH O2
P450
Pyrazole
Aminotriazole
Acetaldehyde
Mitochondrion
AlDH
NAD+
NADH
Disulfiram
(antabuse)
Chlorpropamide
(diabetes)
Acetate
Extra-hepatic tissue

4. Pathway Perturbations
Glc
G6Pase
F16BPase
G6P GK
Cytosol
F6P
F16BP
PFK
Protein
Ala
ALT
OAA
Asp
AST
PEP
PEPCK
OAA
MDH
NAD+
NADH
Lactate
LDH
NAD+
Pyr PK
Malate
MDH
NADH
NADH
NADH PC
PDH
Acetyl CoA FA
β-Ox
NADH
Malate
OAA
MDH
NAD+
Cit
ICit
NADH
Malate
Suc
Fum
Mitochondrion
αKG
IDH
NAD+
S CoA
αKGDH
NAD+
NADH
NADH

5. Regulation in Skeletal Muscle
PKA AC
cAMP
ATP Ep
AR
Glc
Glycolysis
G6P PP
ATP
Citrate
Acetyl-CoA
Pyr
F6P
F16BP
PEP
Ca2+
PKa
PFK-2
F26BP
NH4+
AMP Pi Pi
IMP
AMP
PFK-1
Glycogen
Glycogenolysis
b-Oxidation
Ca2+
PDHP
PDHK
PDH
Fatty acids PK
PDH

6. Glycogen Storage Disease Type VII (Tarui Disease)
Classic, infantile onset, Late onset
Exercise intolerance, fatigue, myoglobinuria
Phosphofructokinase
Tetramer of three subunits (M, L, P)
Muscle/heart/brain - M4; liver/kidneys - L4; erythrocytes - M4, L4, ML3, M2L2, M3L
General symptoms of classic form
Muscle weakness, pronounced following exercise
Fixed limb weakness
Muscle contractures
Jaundice
Joint pain
Laboratory studies
Increased serum creatine kinase levels
No increase in lactic acid levels after exercise
Bilirubin levels may increase
Increased reticulocyte count and reticulocyte distribution width
Myoglobinuria after exercise
Ischemic forearm test - no lactate increase with ammonia increase

7. Pyruvate Dehydrogenase Complex Deficiency
Neonatal, infantile, childhood onset
Abnormal lactate buildup (mitochondrial disease)
Pyruvate dehydrogenase complex
E1 -  (thiamine dependent) and  subunits, 22 tetramer
E2 - monomer (lipoate dependent)
E3 - dimer (riboflavin dependent) common to KGDH and BCAKDH
X protein - lipoate dependent
Pyruvate dehydrogenase phosphatase
Nonspecific symptoms (especially with stress, illness, high carbohydrate intake)
Severe lethargy, poor feeding, tachypnea
Key feature is gray matter degeneration with foci of necrosis and capillary proliferation in the brainstem (Leigh syndrome)
Infants with less than 15% PDH activity generally die
Developmental nonspecific signs
Mental delays
Psychomotor delays
Growth retardation
Laboratory studies
High blood and cerebrospinal fluid lactate and pyruvate levels
Elevated serum and urine alanine levels
If E2 deficient, elevated serum AAs and hyperammonemia
If E3 deficient, elevated BCAA in serum, KG in serum and urine

8. Maple Syrup Urine Disease (Branched-Chain -Ketoaciduria)
Classic (early) and late onset (5 clinical phenotypes; classic, intermediate, intermittent, thiamine-responsive, and E3-deficient)
Encephalopathy and progressive neurodegeneration
Branched-chain -ketoacid dehydrogenase complex
E1 -  (thiamine dependent) and  subunits, 22 tetramer
E2 - monomer (lipoate dependent)
E3 - dimer (riboflavin dependent) common to KGDH and PDH
BCKD kinase
BCKD phosphatase
Initial symptoms
Poor feeding, vomiting, poor weight gain, and increasing lethargy
Neurological signs
Alternating muscular hypotonia and hypertonia, dystonia, seizures, encephalopathy
Laboratory studies
Elevated BCAA in serum
Presence of alloisoleucine in serum
Presence of -HIV, lactate, pyruvate, and KG in urine
Treatment
Restriction of BCAA
Supplementation with thiamine