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Key points biochem Block 2

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Maria Lopez Barazarte
MD2
Block 2: Quiz 2 biochem notes
Lecture 7: Bioenergetics 2
- Cytochrome c: cytochrome c is the only one not fixed to the imm. Is the bridged bt
complex 3 and 4
- Complex 2 is the only one that does not pump hydrogens - this complex bypasses
complex 1
- Need succinate → fumarate (from TCA) for complex 2 (succinate bypasses complex 1,
electrons directly to CoQ)
- NADH for complex 1 of ETC ( produced from the oxidation of glycolysis, FA oxidation,
ketones metabolism, and TCA)
- Vitamin B2 (riboflavin) constituent of FMN and FAD is needed for complex 1 and 2
- Vitamin B3 (niacin) a precursor of NAD+ complex 1
- Copper required for cytochromes a and a3 in complex 4
- Iron required for cytochromes and Fe-S centers
- Sulfur required for Fe-s centers
-
Complex 1 inhibitors: rotenone (pesticides, fish poisoning), barbiturates (amytal,
hypnopic)
Complex 2 inhibitors: malonate
Complex 3 inhibitors: antimycin
Complex 4 inhibitors (cytochrome a,a3): cyanide (byproduct of nitroprusside), CO
Complex 5 / atp synthase (ATP production): oligomycin
ADP/ATP translocase: atractyloside (herbicide)
Maria Lopez Barazarte
MD2
Thermogenin is a proton channel present in uncoupler humans, allowing protons reentering to
MM from IMS independent of ATP synthase. Is found in brown fat of newborns to generate heat
Recall that ATP synthase takes all those protons and pumps them back in
-
mtDNA (from mom) is 10 times more susceptible to mutations than nuclear DNA
Mitochondrial encephalopathies affect the tissues with high rate of oxidative
phosphorylation (muscle - skeletal and cardiac, brain, eyes, liver, kidneys)
Mitochondrial myopathies are tissue specific, some affect heart other muscle, major
symptom is lactic acidosis
Leber’s hereditary optic neuropathy (LHON): sudden onset of blindness (15-35 y/o)
degeneration of optic nerve
Disorders hints in vignette:
- MELAS: lactic acid accumulation, incoordination, muscle weakness, seizures
Maria Lopez Barazarte
MD2
Lecture 8:
Gluconeogenesis: synthesis of glucose from non carb
Main precursors: lactate, pyruvate, glycerol and glucogenic AA such as alanine
- PHD for insulin world
- Pyruvate carboxylase for glucagon world
DOES NOT OCCUR IN SKELETAL MUSCLE BECAUSE OF LACK OF G6P
DOES NOT OCCUR IN HEART MUSCLE BECAUSE OF DEF PF F1,6BP
CORI cycle links anaerobic glycolysis and exercising muscles to gluconeogenesis in the liver →
prevents lactate accumulation
Lactate is picked up by the liver. Muscle fatigue is caused by accumulation of lactate
-
Pyruvate carboxylase (PC)needs biotin as a cofactor in the reaction of pyruvate to OAA
OAA is transported through the malate shuttle because is polar and cant pass
Maria Lopez Barazarte
MD2
-
ATP is needed as a cofactor for PEPCK to convert OAA to PEP
GLU-6-P only in the liver and kidney. NO MUSCLE. Required for glycogenolysis and
gluconeogenesis
CLINICAL CORRELATES
1. Pyruvate carboxylase deficiency: Fast state. accumulation of pyruvate, severe lactic
acidosis because of increase in lactic acid, fasting hypoglycemia. LAB: increase blood
lactate, increase blood pyruvate. In urine, high alanine, citrulline and lysine.
Hyperammonemia (decreased urea cycle), and ketonemia
- Most individuals present failure to thrive, developmental delay, recurrent
seizures, hypotonia, intellectual disability, metabolic acidosis
- RX: high carb, high protein diet to prevent gluconeogenesis. Avoid fasting
and keto diet
- Biotin deficiency
2. Pyruvate dehydrogenase deficiency: fed state. blood lactate, pyruvate, and alanine
are elevated. Glucose is normal. Low atp levels _ low citrate. No ketone bodies detected.
- Rx: low carb diet, high fat keto diet
3. Biotinidase deficiency: not able to recycle biotin. Which is a cofactor for PC. acidosis
(mild), rashes (dermatitis), brittle hair, hair loss. RX: biotin replacement
4. PEPCK deficiency: defective gluconeogenesis, hypoglycemia, failure to thrive, loss
muscle tone, hepatomegaly
5. Von Giere disease (type 1 glycogen storage disease): mutation on G-6-P
6. Fructose 1,6 biphosphate deficiency: lactic acidosis and hypoglycemia
- When energy charge of the cells is low, glycolysis is favored, and gluconeogenesis is
inhibited and vice versa
- Fructose 2,6 bisphosphate is the most important allosteric modulator of glycolysis and
gluconeogenesis
Alcohol metabolism - 3 routes
** most important route: Ethanol --(ADH)--> acetaldehyde --(ALDH)--> acetic acid
- Acetaldehyde is toxic → causes nausea and vomiting
- NAD+ is a cofactor for both ADH and ALDH → gets reduced to NADHH+ (leading
to high levels of NADH++)
- Acetate generated enters the blood
- Ethanol and methanol are competitive inhibitors
Maria Lopez Barazarte
MD2
-
Fomepizole inhibits ADH
Disulfiram inhibits ALDH - prescribed for recovering alcoholics. Inactive ALDH
causes dislike for alcoholic beverages
- Alcohol consumption can cause hypoglycemia. High NADH++ generated favors
other conversions (pyruvate to lactate → lactic acidosis, OAA to malate →
decreases OAA to gluconeogenesis).
- Fatty liver due to accumulation of NADHH+ and glycerol 3P + excessive acetic
acid
- ****Hypoglycemia, lactic acidosis, hyperlipidemia and ketoacidosis are
common findings in alcoholics
- Alcohol inhibits active transport of thiamin → thiamine def in alcoholics (Wernicke
korsakoff syndrome). Confusion, ophthalmoplegia, ataxia.
Hints from questions:
- Depletion of Hepatic glycogen stores → lactate would be present
- Low carb, high fat diet, how do we produce glucose? - using glycerol
Kinases are activated by dephosphorylation
Lecture 9:
Glycogen is stored in cytosol granules of:
1. Liver: maintain the normal blood glucose concentrations
2. Muscle: do not contain G-6-pase. G6P stays inside the muscle cells a a local source of
energy during muscle contraction. Do not use for maintain the normal blood glucose
concentration
Trapping and activation of glucose:
- Glucose transformed to G6P by hexokinase / glucokinase → from glycolysis
- glucokinase/hexokinase reaction (traps glucose as G6P inside of the cells).
- phosphoglucomutase (PGM) reversibly isomerizes G6P to G1P.
- UDP-glucose pyrophosphorylase transfers G1P to UTP, which generates
UDP-glucose (the active form of glucose)
- UDP GLUCOSE IS THE IMMEDIATE PRECURSOR FOR GLYCOGEN SYNTHESIS,
PROTEOGLYCANS/ GLYCOLIPIDS/ GLYCOPROTEINS
Maria Lopez Barazarte
MD2
For the formation of the linear structure of glycogen
- Glycogen synthase the rate limiting enzyme transfer/attaches glucose from
UDP-glucose onto the non reducing end of the primer by formation of alpha 1-->4
glycosidic bond making a linear polyglucose chain called amylopectin. CAN
ONLY USE UDP GLUCOSE FOR THE CHAIN
For the branching
- RXN: amylo-(1,4 → 1.6) transglycosylase/ glucosyl. Enzyme: 4:6 transferase. Alpha
1.6 linkages make the branches
For degradation
- Glycogen attacked by debrancer enzyme → releases a little bit of glucose → attacked by
glycogen phosphorylase and Pi→ changed to Glucose 1-P→ phosphoglucomutase
transforms it to glucose 6-P → G-6-Pase (ONLY LIVER) transforms it to glucose
- Chain shortening by release of G1P
- Glycogen phosphorylase uses inorganic phosphate (Pi) to attack nonreducing ends
Debranching enzyme
- Transferase domain: transfer residues from outer branch to another
- ******Alpha 1,6 glucosidase domain (hydrolase activity): cleaves alpha 1-->6
glycosidic bond and release free glucose
- The small amount of glycogen is degraded by lysosomes by acid maltase / lysosomal
a-glucosidase (hydrolyzes both a-1,4 and a1,6) to get glucose
Maria Lopez Barazarte
MD2
The control of glycogen metabolism is needed to maintain physiological blood glucose level and
provide energy for exercising muscles
- FED/ glycolysis: glycogen synthase is ON (because we want to make reserves)
- FAST/ glycogenolysis: glycogen phosphorylase is ON (because we need some source of
energy - from storage / reserve) to feed the muscle. - GLYCOGENOLYSIS BY
EPINEPHRINE AS IN ACUTE STRESS OR EXERSICES (muscle does not have
receptors for glucagon).
CLINICAL CORRELATION - glycogen storage diseases (GSD)
1. GSD type 0: Glycogen synthase deficiency. This enzyme uses UDP to make the
alpha 1→ 4 bonds. So no storage of glycogen because there is no chain elongation. In
the liver, there is hyperglycemia after meals, and in the muscle there is fatigue and
muscle cramps.
2. GSD Type I: Von Gierke disease: Glucose-6-Pase. Problems in dephosphorylation
of Glc-6-P to Glucose.
- Hepatic form. Hypoglycemia. Hepatomegaly. Person does not respond to
epinephrine or fructose. Slightly acidic blood pH, elevated ketones, triglycerides,
cholesterol, and liver enzymes. DOLL LIKE FACE. Normal structure glycogen is
biopsy.
- Avoid fasting, high carb diet
3. GSD Type II; Pompe disease: lysosomal a glucosidase / acid maltase defective.
Problems in lysosomal attack to release glucose.
- Progressive muscle weakness, congestive heartfailure and enlarged heart. No
rolling, baby is flaccid, flops back when lifted - FLOPPY BABY. increase glycogen
stores in lysosomes. Normal lactate (no acidosis), no hypoglycemis, increase CK,
AST, LDH
4. GSD type III: Cori disease. Defective debranching enzyme (amylo 1,6 glycosidase)
- Irritability, failure to thrive. Mild fasting hypoglycemia. High protein diet or fructose
increases glucose concentration. Hepatomegaly Biopsy shows increased amount
Maria Lopez Barazarte
MD2
5.
6.
7.
8.
of glycogen with short outer branches. - increased abnormal glycogen with many
branch points
GSD type IV: Andersen
disease: branching enzyme deficiency (amylo 4,6
glucosidase). Abnormal glycogen with few branches in the liver. Long linear glycogen
without or few branches, amylopectin.
- Hepatomegaly, cirrhosis, cardiomyopathy, begin the first months of life. Liver
becomes cirrhotic.
GSD Type V: McArdle disease. Defective glycogen phosphorylase. Problems with
Glc 1-P release.
- Myopathy. Increased fatigue and muscle pain in legs after exercise. lactate
concentration remains decreased/ same in blood after exercise. Accumulation of
normal glycogen in muscle tissue. Normal blood glucose. Burgundy colored urine
after exercise.
- Rx: admi of glucose before exercise
GSD type VI: Hers disease. Glycogen liver phosphorylase is defective. Problems
with Glc 1-P release in liver
- Hepatomegaly, hypoglycemia, symptoms present at young age, nomral lactic an
uric acid
GSD Type VII: Tauri disease. Mutation in muscle PFK-1.
- Myopathy. Severe exercise intolerance, trouble with anaerobic activities, lack of
lactate production, hemolytic anemia. Defective isoenzyme M in PFK-1 in
muscle. Normal blood glucose.
Hepatic forms: 1,3,4,6 - hepatomegaly, hypoglycemia, lactic acidosis, hyperuricemia,
hyperlipidemia
Myopathic forms: 5 and 7 - muscle cramps, pain, fatigue upon exertion
Lysosomal: 2 - POMPE all organs involved, specially myocardium, skeletal muscle, liver, motor
nuclei of spinal cord
Hyperuricemia is caused by lactate inhibition of kidney tubule excretion or urate
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