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)