Metabolism Part II Flashcards
What are the 4 fates of pyruvate?
- Acetyl CoA
- Oxaloacetate
- Alanine
- Lactate
What enzyme converts pyruvate to Acetyl CoA
Pyruvate Dehydrogenase
What factors regulate pyruvate dehydrogenase?
TLC for Nobody Thiamine pyrophosphate (TPP) - active B1 Lipoic acid Coenzyme A - B5 FAD - B2 NAD+ - B3
What B vitamins are needed to make Acetyl CoA?
B1, B2, B3, B5
What factor does arsenic inhibit
Lipoic acid - cofactor for PDH
Arsenic poisoning features
Garlic breath, vomiting, rice water stool
What happens in PDH deficiency and what clinical features result
Back up of pyruvate that gets converted to other things: Lactate, Alanine.
Lactic acidosis
Neurologic defects
What is treatment of PDH deficiency
Increase intake of ketogenic nutrients (high fat, high lysine and leucine) - so can make Acetyl CoA from something else. Ketone bodies can be used for energy instead of glucose.
How is PDH deficiency acquired?
Arsenic exposure, B vitamin deficiency (especially B1)
What does TCA enzyme citrate synthase do
Makes citrate from Acetyl CoA and oxaloacetate
What does isocitrate dehydrogenase do
Converts isocitrate into alpha ketoglutarate
What is the rate limiting enzyme in the TCA cycle
Isocitrate dehydrogenase
What does alpha ketoglutarate dehydrogenase do
Converts alpha ketoglutarate to succinyl-CoA
Why is alpha ketoglutarate dehydrogenase so regulated
Requires same cofactors as PDH complex: TPP, lipoic acid, coenzyme A, NAD, FAD+
How many moles of ATP are produced per NADH in ETC?
2.5
How many moles of ATP are produced per FADH2 in ETC?
1.5
What effect does Amytal (a barbiturate) have on ETC?
Blocks Complex I
What effect does Rotenone have on ETC?
Blocks Complex I
What effect does MPP have on ETC?
Blocks Complex I
What effect does Antimycin A have on ETC?
Blocks Complex III
What effect does CN have on ETC?
Blocks Complex IV
What can inhibit complex IV of the ETC?
CO, N3-, CN, H2S (hydrogen sulfide)
What can inhibit the ATPase of ETC?
Oligomycin A (macrolide antibiotic)
What affect do uncoupling agents have on inner mitochondrial membrane
Make it more permeable to H+ ions - generate more heat in the bottom
What is thermogenin
An uncoupling agent for heat in hibernation - found in brown fat
What are some uncoupling agents?
Aspirin
Thermogenin
2,4-Dinitrophenol
What enzymes convert lactate and pyruvate?
Lactate dehydrogenase
What happens to lactate in the liver
Lactate (from anaerobic glycolysis in muscles, RBCs) gets converted back to pyruvate via LDH.
Pyruvate can be used for gluconeogenesis.
How are the alanine cycle and cori cycle similar?
Muscles make something that goes to the liver to be made into glucose
Describe steps of alanine cycle
Pyruvate gets converted to alanine in muscle It goes in serum to liver, where it is uptaken, converted back to pyruvate -> glucose
Why are alanine and glutamine found in such high concentrations in the blood?
Ala and glutamine are two major carriers of nitrogen from tissues. Liver uses glutamine to make urea.
What is generally involved in transamination?
transfer of amino group of an amino acid to alpha ketoglutarate to form glutamate.
the remaining deaminated amino acid is a ketoacid (eg pyruvate) that is used in energy metabolism
What enzyme catalyzes transamination?
Aminotransferases
How are aminotransferases named?
By donor of the amino group (alanine aminotransferase converts alanine to pyruvate and forms glutamate)
In addition to substrates, what is required by all aminotransferases?
Pyridoxal phosphate (a derivative of B6)
What are the substrates and products of alanine aminotransferase?
Alanine+aKG -> Glutamate + Pyruvate
What are the substrates and products of aspartate aminotransferase?
Aspartate+aKG -> Glutamate + oxaloacetate
What are the two main carriers of nitrogen in the blood?
Alanine + Glutamine
What is NADPH needed for? 4 reasons
Make FA’s and Cholesterol
Make O2 free radicals
Inside RBCs to protect from O2 free radicals
Cytochrome p450
Most important enzyme of the HMP shunt
G6PD
What does G6PD do
Converts G-6-P to Ribulose 5-P and get 2 NADPH
What is needed to create oxygen free radicals
Oxygen, NADPH, and NADPH oxidase
What converts free radical oxygen to hydrogen peroxide
Superoxide dismutase
What does myeloperoxidase do
Converts hydrogen peroxide to hypochlorus acid HOCl
What disease results from deficiency of NADPH oxidase
Chronic granulomatous disease - susceptible to catalase positive organisms because neutralize environmental hydrogen peroxide to water
What does glutathione peroxidase do
Converts hydrogen peroxide into water, by letting H2O2 react with reduced glutathione (GSH)
What is reduced glutathione
An antioxidant required to neutralize H2O2 into water
How is glutathione disulfide converted back to reduced glutathione?
Glutathione reductase
What does glutathione reductase use as an electron donor
NADPH (to reduce glutathione)
What keeps the steady supply of NADPH around in order to continue to reduce glutathione for antioxidation?
G6PD
What are some drugs that “oxidize” red blood cells and so are problematic in G6PD deficiency (-> hemolytic anemia)
Anti malarial drugs primaquine and chloroquine Nitrofurantoin Dapsone Sulfonamide Isoniazid Naphthalene (moth balls) Fava beans Ibuprofen High dose ASA
What enzyme is deficient in essential fructosuria
Fructokinase
What enzyme is deficient in fructose intolerance
Aldolase B
Why is essential fructosuria benign
Fructose doesn’t get trapped in cells - have it spilling out into blood and urine
What is pathophysiology of fructose intolerance/ aldolase B deficiency?
Cannot correct fasting hypoglycemia - accumulation of fructose 1-P in cells causes decreased available phosphate(using it up), inhibits glycogenolysis and gluconeogenesis.
What are clinical symptoms of fructose intolerance
Hypoglycemia
Vomiting - after fructose or sucrose
Hepatomegaly, jaundice
What enzyme is deficient in galactokinase deficiency
Galactokinase - can’t convert galactose to galactose-1-p
What is pathophysiology and clinical features of galactokinase deficiency
Galactose converts to galactitol which accumulates in the blood and can appear in blood and urine, cause infantile cataracts
What enzyme is deficient in classic galactosemia
Absence of galactose-1-phosphate uridyltransferase
Pathophysiology of classic galactosemia
Accumulation of toxic substances galactose-1P and galactitol
Clinical features of galactosemia
Hepatomegaly, jaundice, FTT, infantile cataracts, intellectual disability
What is the treatment for galactosemia
Exclude galactose and lactose from diet
Rate limiting step of pentose phosphate pathway
G6PD
Which tissues use pentose phosphate pathway
RBCs, Liver, Adrenal cortex, Mammary glands (during lactation)
What disease is caused by deficiency of galactokinase
Galactokinase deficiency
What disease is caused by deficiency of aldolase B deficiency
Fructose intolerance
What disease is caused by deficiency of galactose-1-phosphate uridyltransferase
Classic galactosemia
What disease is caused by deficiency of fructokinase
Essential fructosuria
What is the primary energy source in a patient who has not eaten in 2 days
Fatty acids
Rate limiting enzyme in ketone body synthesis
HMG CoA synthase
Why do people get hypoglycemic after drinking alcohol?
NADH produced which shunts pyruvate toward production of lactate, shunts oxaloacetate toward production of malate, so pyruvate and oxaloacetate are not available to undergo gluconeogenesis
Hallmark features of Kwashiorkor
FLAME Fatty Liver Anemia Malnutrition (protein) Edema Skin lesion, skin and hair depigmentation
When does gluconeogenesis start in the post-absorptive period?
Starts 4-6 hours after last meal
Full active when glycogen stores are depleted
When are glycogen stores depleted
10-18 hours
What are the two main ketone bodies made in the liver
Acetoacetate and Beta-hydroxybutyrate are made from fatty acids and amino acids using NADH
What causes fruity breath smell in ketosis
Acetoacetate spontaneously becomes acetone
What does urine test for ketones test for
Acetoacetate only
When do you start making ketones?
When you have so many fatty acids and so much acetyl coA that TCA cycle can’t handle it all;
Oxaloacetate depleted for gluconeogenesis
What metabolic scenario favors synthesis of ketone bodies
When production of acetyl CoA from beta oxidation of FA’s exceeds oxidative capacity of the TCA cycle
What is marasmus
Total energy malnutrition (deficient in everything)
What is refeeding syndrome
Drop in serum Mg, Phosphate, and K+, can lead to arrhythmias and neurologic problems
Overall ATP depletion - phosphorylating glucose in cells depletes it.
