8/22/17 Flashcards
Shuttle for NADH
Get NADH reductive potential from cytoplasm into the mitochondria
Malate-Aspartate shuttle
Glycerol 3-Phosphate shuttle
Arsenic poisoning
Arsenate looks like phosphate and ruins enzyme linked glyceraldehyde 3-P dehydrogenase
Arsenite allosterically inhibits pyruvate dehydrogenase
Lactic acidosis
Pyruvate to lactate by lactate dehydrogenase to recycle NADH
Due to lack of oxygen, cyanide poisoning, Von Gierke disease of impaired pyruvate oxidation, leukemia and metastatic carcinoma that has anaerobic respiration by neoplastic cells
Pyruvate kinase deficiency
Many mutations, commonly but not always autosomal recessive
Expressed in erythrocytes so rely on reticulocytes
Cause chronic hemolytic anemia:
Lack ATP for Na/K ATPase so lead to swelling and rigidity of RBCs, gallstones, splenic hemolysis
Second most common enzyme deficient hemolytic anemia behind Glu 6P dehydrogenase, no malaria resistance, increased 2,3 BPG levels to decrease glycolysis and help the anemia
Treatment: blood transfusions, splenectomy, iron chelation, bone marrow transplant
Pyruvate dehydrogenase deficiency
Pyruvate and lactate accumulate, less ATP
X-linked mutations on the E1 alpha gene
Thiamine cofactor
Clinical heterogeneity, esp. for females
Metabolic form causes severe lactic acidosis, cells with good copy of gene though can buffer against
Chronic neurological form has mild lactic acidosis but brain dysfunction and structural abnormalities
Treatment: high fat/low carb (ketogenic diet), thiamine supplement, sodium bicarbonate and citrate to treat acidosis, dichloroacetate to inhibit E1 regulatory kinase that inhibits the PDH
What the brain does not use for energy
No fatty acid breakdown, use glucose and ketone bodies
Pyruvate Carboxylase Deficiency
Add CO2 to pyruvate to make oxaloacetate, use biotin
Rare autosomal recessive, three types
Build up of pyruvate (lactic acidosis)
Hypoglycemia (decreased gluconeogenesis)
Decrease in myelin sheath and neurotransmitters (anaplerotic effects)
Lactic acidosis, failure to thrive, seizures
Biotin, triheptanion, citrate for acidosis, aspartate for urea cycle, high carb and protein diet to avoid gluconeogenesis (avoid ketogenic diet)
Acute cyanide poisoning
CN- blocks electron transport by binding ferric (Fe3+) in cytochrome oxidase (Complex IV)
Hyperventilation from lactic acidosis from switch to glycolysis
Nitrite used to oxidize Hemoglobin to methemoglobin (Fe3+), binds cyanide tightly to remove from Complex IV
Rhodanase in 5he liver normally reacts cyanide with thiosulfate to make thiocyanate
Kearns-Sayre Syndrome
Deletions of tRNA and oxidative phosphorylation genes
Late onset ptosis, opthalmoplegia
Myopathic facies and a hearing aid in example,
looks like stoner
MERRF
Myoclonic Epilepsy and Ragged-Red Fiber disease
Mutation in mtDNA gene MT-TK for tRNA Lys
Late onset
Myoclonic epilepsy (muscle twitching), short, hearing loss, lactic acidosis, exercise intolerance, progressive dementia
Clumps of diseased mitochondria appear in muscle fibers (stain red)
No good treatment but CoQ-10 and L-carnitine may be attempted
Leber’s Hereditary Optic Neuropathy (LHON)
Sudden blindness in young adults caused by degeneration of Erin all ganglion cells of optic nerve
Three different types of mutations to NADH dehydrogenase (Complex I)
Mainly males, Northern European
Idebenone: boosts ETC, bypasses Complex I, experimental treatment
MCAD deficiency
Medium chain acyl-CoA dehydrogenase
First enzyme of beta oxidation, inability to break down C6-C12
Elevated dicarboxylic acids in urine
Acute energy deficiency, sudden hypoketotic hypoglycemia triggered by illness or fasting, can include seizure, coma, and death
Caused by a mutation, clinical heterogeneity
Avoid fasting, do glucose supplementation, low fat diet, prognosis ok if get early but may cause SIDS
VOMIT AAs: Val, Met, Ile, Thr
CPT II Deficiency
Carnitine palmitoyltransferase II
Catalyze last step of LCFAs into the mitochondrial matrix
Acute myglobinuria (brown urine) from exercise, fasting, or illness
Adult type: rhabdomyolysis (breakdown of muscle fibers, release of myoglobin), mild, myopathic
Infantile type: severe hypoketonic hypoglycemia, liver failure, cardiomyopathy
Neonatal: lethal within days, respiratory failure, hypoglycemia, seizures
Treatment: avoid fasting/extreme exercise/lipid intake, do high carb and low fat diet, carnitine supplementation, Triheptanoin for energy source
Propionyl-CoA associated disorders
Build up of toxic intermediates (organic acids) of oxidation of odd number FAs
Propionic acidemeia and methylmalonic aciduria (enzyme or B12 deficiency)
Poor feeding, lethargy, acidosis, seizures, can be life threatening
Low protein diet, specialized AA formulas, antibiotics for gut bacteria that make propionic acid
Peroxisome Roles
Oxidation of VLCFA and branched FAs
Synthesis of plasmologens and bile acids
Catabolism of D- amino acids and polyamines
Two enzymes for the PPP
Neutralize toxic substances
X-linked Adrenoleukodystrophy
Defect in ABCD1 gene that encodes a protein to transport VLCFAs into peroxisomes, they accumulate in tissues and damage myelin sheath/adrenal cortex
Progressive motor dysfunction and adrenal insufficiency
Cerebral demyelinating form: childhood, inflammatory demyelination with rapid progress to a vegetative state
Adrenomyeloneuropathy: young adults, non-inflammatory distal axonopathy with gradual progression to a spastic paraplegia
Lorenzo’s oil: special mix of unsaturated lipids that tried to clog up chain elongation machinery, doesn’t slow down disease progression
