Eric Niederhoffer SIU-SOM SSB End of Unit Review.
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Transcript of Eric Niederhoffer SIU-SOM SSB End of Unit Review.
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, PFK2Inhibitory: 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
Mitochondrion
Peroxisome
EtOH
Acetaldehyde
Acetate
Cytosol
ER
ADH
NAD+
NADH
CAT
H2O2
H2O
AlDH
NAD+
NADH
MEOS
NADP+
NADPH
O2
P450
Extra-hepatic tissue
Oh my!Now what?
Pyrazole
Disulfiram(antabuse)
Chlorpropamide(diabetes)
Aminotriazole
Cellular Processing
Glc
Prote
in
Ala
ALT
MalateMDH
NADHNADH
Malate
PEPCK
G6PGK
F6P
F16BP
PFK
PEP
Pyr
PK
NADH
Malate
Suc
Fum
PDH
Acetyl CoA
Cit
ICitMitochondrion
Cytosol
NADH
NADH
PC
OAA
Asp
ASTOAA
MDH
NAD+
OAAMDHNAD+
αKG
IDHNAD+
LactateLDH
NAD+
S CoA
αKGDHNAD+
G6Pase
F16BPase
NADH
FAβ-Ox
NADH
Pathway Perturbations
NADH
Fatty acids
b-Oxidation
Glc Glycolysis
GlycogenGlycogenolysis
PDH
PK
PFK-1
PKA
ACcAMP ATP
Ep
AR
Acetyl-CoAPyr
F6P
F16BP
PEP
PiIMPAMP
NH4+
AMPPi
Ca2+
PKa
G6P
PP
Ca2+
PDHPPDHK
PDHP
PDH
PFK-2
F26BP
ATPCitrate
Regulation in Skeletal Muscle
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
Glycogen Storage Disease Type VII (Tarui Disease)
Neonatal, infantile, childhood onset
Abnormal lactate buildup (mitochondrial disease)
Pyruvate dehydrogenase complex
•E1 - (thiamine dependent) and subunits, 22 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
Pyruvate Dehydrogenase Complex Deficiency
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, 22 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
Maple Syrup Urine Disease (Branched-Chain -Ketoaciduria)