Week 3 Flashcards
(142 cards)
Beta oxidation.
Substrates, product, location, transport mechanisms
Long chain fatty acids are carried by albumin in blood, carried into cell by fatty acid binding proteins.
Fatty acyl coA synthetase attaches CoA to FA. Carnitine then shuttles the FA into the mitochondrial matrix where it is reattached to CoA.
B-oxidation cleaves fatty acyl CoA to generate acetyl CoA, NADH, FADH2.
Acetyl coA enters CAC or is made into ketone bodies
Common themes in metabolic disorders
Many diseases have multiple types/forms
Loss of enzymes cause back up in pathways.
Certain tissues will exhibit increased sensitivity to certain types of enzyme deficiency
Dietary strategies and supplementation of cofactors can often alleviate symptoms
Lactic Acidosis
Not an enzyme disorder, but a symptom of many enzyme disorders.
Build up of pyruvate shunts to lactate dehydrogenase and a build up of lactic acid.
Happens when CAC or respiration is blocked or overwhelmed.
Physical exercise, hypoxic/anaerobic conditions, anemia, CO or CN poisoning, alcohol intoxication, pyruvate dehydrogenase deficiency.
Can often be treated with bicarbonate or citrate
Pyruvate kinase deficiency
affects on biochem, symptoms, treatment
Dysfunctional last step of glycolysis. Little pyruvate made.
Hemolytic anemia results because RBC rely heavily on glycolysis (no mitochon) for energy and this affects the isozyme found in RBC.
Also results in jaundice, splenic hemolysis(and subsequently splenomegaly) gallstones, infection.
Lack of energy in RBC cause swelling
and rigidity because of lack of ATP for ion transport.
Back up results in build up of 1,3-BPG and conversion to 2,3-BPG which alleviates some of the anemia but also inhibits hexokinase further exacerbating glycolysis deficiency.
Treatments include blood transfusion, splenectomy to lower hemolysis, iron chelation, marrow transplant to fix RBC production.
Pyruvate dehydrogenase deficiency
Effects on biochem, symptoms, treatment
Deficiency in pyruvate oxidation/production of acetyl-CoA. ATP decreases and pyruvate builds up (lactic acidosis)
Majority of mutations affect the E1aplha subunit encoded on the X-chromosome. Different presentation in males and females typically
Metabolic form (severe) results in overwhelming lactic acidosis (fatal)
Chronic neurological form is milder (prominent in females). Moderate acidosis, but severe brain dysfunction with abnormal development. Brain relies heavily on glucose oxidation for normal development/energy.
Ketogenic diet can provide ketones for brain fuel. Thiamine supplementation (cofactor) can promote what enzymes are present.
Bicarbonate and citrate for acidosis
Dichloroacetate inhibits E1 inhibitor to promote reaction.
Pyruvate Carboxylase deficiency
Biochem, symptoms, treatments
Pyruvate not converted to oxaloacetate.
- high pyruvate (lactic acidosis)
- Low oxaloacetate (hypoglycemia due to decreased gluconeogenesis)
- anaplerotic effects result in decrease in myelin sheathing and neurotransmitters. (Neuro dysfunction)
- recurrent seizures, developmental delays
No effective treatments.
- Attempt to hydrate,
- Avoid gluconeogen-administer glucose or high carb diet to promote pyruvate formation, avoidance of fasting or ketogenic diets
- apsartate to promote oxaloacetate
- Biotin supplementation
Cyanide poisoning
Cyanide binds to Fe3+ on cytochrome oxidase to block ETC.
Massive lactic acidosis due to switch over to anaerobic pathways. Results in hyperventilation. Weak acid form HCN is highly diffusible.
Treat with nitrite. Nitrite oxidizes hemoglobin from Fe2+ to Fe3+ (methemoglobin). Binds cyanide tightly and steals form cytochrome oxidase.
Small amounts obtained from diet can be metabolized by rhodanase in liver. Binds CN and thiosulfate to form thiocyanate.
Oxphos disease characteristics and causes
Mutations in mitochondrial DNA. Maternal inheritance and can be a result of heteroplasmy (unequal segregation of different mitochon genotypes during mitosis/meiosis)
Mitochon DNA also haas a high mutational rate due to inability to repair DNA. These diseases have a late onset b/c waiting for accumulation of mutation.
Most prevalent in tissue with high mitochondrial count skeletal and cardiac muscle, retina
Typical mitochon diseases
MELAS LHON Kearns-Sayre syndrome NARP MERRF Pearson syndrome Leigh disease
MCAD NOT INCLUDED
Kearns-Sayre Syndrome
Symptims include bilateral ptosis (impaired eyelid movement), Opthalmoplegia (impaired eyeball movement)
Deletions of tRNA and oxphos genes in mitochondria
MERRF
Myoclonic Epilepsy with ragged red fibers
Mutated tRNAlys. CLumps of diseased mitochon appear in muscle stain
Progressive twitching of muscles(myoclonic epilepsy)
Late adult onset
Can use coenzyme Q-10 (respiration) and L-carnitine (FA transport into mitochon) to help ease symptoms, but no effective treatment.
LHON
Oxphos disease Leber’s Hereditary Optic Neuropathy.
Sudden acute blindness in young adults caused by degeneration of retinal ganglia in optic nerve. Optic nerve has high energy demand and relies heavily on Oxphos.
Higher prevalence in males, caused by mutations in complex I (NADH dehydrogenase) of ETC. Most people with mutation never experience symptoms.
Idebenone-bypasses complex I in ETC
MCAD deficiency
Medium chain acyl CoA dehydrogenase.
Impaired ability to breakdown medium chain (C6-C12) fatty acids in mitochondrial matrix. Results in acute energy deficiency (presents as hypoketotic hypoglycemia).
Characterized by elevated levels of C8 acylcarnitine(backup in carnitine shuttle), and short dicarboxylic acids (product of omega oxidation in ER) in urine
Presents in healthy children 3-24 months and is triggered by illness or prolonged fasting.
Treatments avoid beta-oxidation and focus on glucose pathways by low fat diet, avoid fasting, glucose supplementation. Can also supplement with carnitine. Was a common cause of SIDS, but now prognosis is excellent of caught early.
CPT II Deficiency
Carnitine palmitoyltransferase II enzyme deficiency.
Impairment of removal of carnitine and replacement of CoA after LCFA transport across mitochondrial intermembrane space.
Characterized by episode of myoglobinuria triggered by exercise, fasting, illness. In adults presents as rhabdomyolysis
Infantile: severe hypoketotic hypoglycemia, liver failure, cardiomyopathy, and peripheral myopathy.
Neonatal:lethal in 1-4 days, resp. Failure, hypoglycemia, seizures, hepatomegaly, liver failure cardiomegaly.
Treated by avoidance of fasting, lipid intake, and extreme exercise. High MCFA diet. Carnitine supplementation
Organic Acidemias
Propionyl-CoA associated disorders.
Odd chain fatty acids result in one propionyl CoA at end of beta oxidation.
Build up of organic acids is toxic.
Can quickly become life threatening. Vomiting, acidosis, hypotonia, seizures, coma, lethargy.
Treated with a low protein diet and specialized amino acid formulas .
Peroxisomal FA oxidation
VLCFA C22< and branched FA metabolism site. In general accumulation of VLCFA and branched FA is toxic.
Disruption of myelin sheath and loss of motor function.
Adult Refsum disease
Defect in metabolism (alpha oxidation) of branched FA phytyanic acid (product of chlorophyll breakdown)
Typically late onset (childhood/adolescence).
Treatment is to avoid phytyanic acid in diet.
Progressive, results in blindness, deafness, neuropathy
Peroxisome metabolism illness
Zellweger spectrum disorder
Defect in peroxisome biogenesis, accumulation of branched and VLC FA
Different severities, most severe is death within 1 year. Less sever forms result in progressive loss of hearing, vision, smell, motor function
X-Linked Adrenoleukodystophy
Defect in transport of VLCFA into peroxisome. Toxic build up and damage to myelin sheath and adrenal cortex.
Adrenal insufficiency and loss of motor function.
X-Linked and females show symptoms later in life.
Direct calorimetry values of macronutrients
Carbs=4 kcal/g
Fats=9 kcal/g
Protein=4 kcal/g
Alcohol=7 kcal/g
Because proteins are completely oxidized, this value is the farthest off from what is obtained for metabolism. In the body the nitrogen is excreted is urea without being further oxidized.
Indirect calorimetry
Estimates caloric yield of certain macros by measuring consumed oxygen, produced CO2, and excreted nitrogen. And then comparing this to theoretical yields.
All three consume similar amounts of O2, but produce different levels of CO2. Carbs are most efficient in terms of oxygen used.
Nitrogen excreted*6.25= total mass of protein metabolized
Respiratory Quotient
RQ= volume CO2 produced/volume of O2 consumed
Theoretical values based on combustion of standard molecule
Carbs=1
Protein=0.8
Fats=0.7
1) determine amount of N excreted and multiply by 6.25
2) determine how much O2 and CO2 are consumed by protein mass (4kcal/g, 4.5kcal/liter O2, RQ=0.8)
3) NPRQ=VtotCO2-VprotCO2
4) Use NPRQ to determine the ratio of carbs to fats being used
RQ is closer to 0.7 when fasting, extended exercise, resting, gluconeogenesis
RQ is closer to 1 when fed, early in exercise, lipogenesis
Fuel consumption during exercise
Muscle glycogen(10 minutes)->liver glycogen (10-20 minutes)-> Fatty acid(>20 minutes)
Glycogen depletion hits around 2 hours, gluconeogenesis can sustain for. Short mount of time afterwards before hypoglycemia.
Energy needs break down
BMR=50-70%
Physical activity= 15-30%
Thermic Effect= 10%
Thermic effect is the energy required to process food.
