TUT 9 Flashcards
(17 cards)
Why do many amino acid disorders lead to mental retardation?
If there is a defect breakdown of amino acid, this AA and their by-product will accumulate in the blood, causing toxic effects to the brain
- Phenylketonuria (PKU) is the defect of phenylalanine hydroxylase causing phe to tyr blocked, phe is transaminated instead to phenyllactate, phenlyacetate and phenylpyruvate excreted
- Those compounds are lipophilc, so it can directly go into membrane –> brain is very protective and sensitive to any change –> lipohilic substance can go into the brain causing mental retardation
- Amino acids are necesssary for protein and neurotransmitter synthesis
Of the disorders that do NOT lead to mental retardation, which one can be detected visually in the urine without any biochemical analysis. Explain.
Alkaptonuria will not lead to mental retardation and can be detected visuallty in the urine without any biochemical analysis
- In people with alkaptonuria, urine darkens. Over a few hours, the urine is oxidised
- Can also bubble oxygen through urine to see if people have alkaptonuria
What special molecules use tryptophan as their template?
Melatonin (sleep inducing hormone) and Serotonin (vasconstrictor) are molecules which use tryptophan as their template
> Serotonin is formed by decarboxylation of 5-Hydroxytryptophan which forms 5 hydroxytryptamine ( serotonin).
>Melatonin is formed from serotonin in a 2 step process; The first reaction of serotonin undergoes the addition of an acetyl group followed by the addition of a methyl group to form melatonin.
How are melanin and adrenaline (epinephrine) related
Melanin and adrenaline are connected by their use of tyrosine in their pathways.
- In both pathways tyrosine via the enzyme tyrosine hydroxylase produces DOPA
- Adrenaline pathways use DOPA to form Dopamine via dopamine carboxylase –> dopamine undergoes beta oxidation to form noradrenaline which uses phenylethanolamine n-methyltransferase to produce adrenaline
What acts as the precursor for histamine generation? What type of reaction generates it, and what other amino acids are also modified via this type of reaction into other local hormones or neurotransmitters?
Formation of histamine is formed by the decarboxylation of histidine via enzyme histidine decarboxylase. Similar aa that undergo decarboxylation are tyrosine. (DOPA use DOPA carboxylase to form dopamine)
tyrosine and methioine also
What are the structural differences and similarities between thyroid hormones (any of them) and Dopamine, both in attributes needed for activity – and how they were constructed?
- Thryoid hormone - contains 2 tyrosine molecule (anabolic), contains an extra element which is iodine
- Dopamine - contains one tyrosine molecule (catabolic)
BOTH made from tyrosine
What is the difference between Carbamoyl phosphate synthase I and II
Carbamoyl phosphate synthase I: deaminated from glutamate, N-acetylglutamate must be present as well to produce carbamoyl phosphate in mitochondria and is involved in the production of urea –> so it is part of the urea cycle and uric synthesis
Carbamoyl phosphate synthase II: In the cytoplasm, work with C02 and NH3 in order to generate carbamoyl phosphate, NH3 source is glutamine and is involved in pyrimidine synthesis
What are all of the components needed to create both AMP and GMP denovo? For example, all the amino acids, gases, cofactors etc (include the number of them needed)
AMP: 2 aspartate, 1 glycine, 2 glutamine, 2 folate derivative, CO2
GMP: 1 aspartate, 1 glycine, 3 glutamine, 2 folate derivates, C02
How do purine salvage pathways work – and why do they exist?
- to limit production of uric acid
- To reduce the energy cost of reproducing GMP and AMP
PRPP= 5 phosphoribosyl-1-pyrophosphate
HGPRT= Hypoxanthine-guanine phosphoribosyltransferase
APRT= adenine phosphroribosyltransferase
Why are small increases in pyrimidine metabolism not as important clinically as small increases in Purine metabolism? However, when considering large changes in pyrimidine metabolism – this becomes clinically relevant again. Why?
purine metabolism: degradation products arent water soluble –> precipitation –> gout (and other inflammatory disorders)
pyrimidine metabolism: degradation products are not important b/c they are water soluble : C02, NH3, beta-aminoisobutyrate
HIGH AMOUNTS OF PYRIMIDINE CATABOLISM LEADS TO
- High (C02) = respiratory acidosis –> hyperventilate
- High (NH3) = toxicity above 40 mm, not packagable into urea (NH3 can only be packaged as urea in liver if ammonia is from glutamate)
- High beta-aminoisobutyrate = large amount of ketone bodies, issue with pH, metabolic acidosis
Describe the end stage regulation of purine synthesis (last 2 divergent steps). What is the purpose of its existence?
Negative regulation:
IMP, AMP, ADP, GMP, GDP is the end product of the two pathways, which are all down-regulated to their own pathway.
Positive regulation:
Too much ATP can inhibit adenylosuccinate synthase synthesis, the more ATP we have, the more it drives to the transaminase reaction and unregulated the GTP synthesis. Too much GTP can inhibit IMP dehydrogenase, the more GTP we have, the more it drives to ATP synthesis.
The cross-regulation between the pathways of IMP metabolism is aim to maintain their balance.
How does methotrexate function – and why is it considered a drug that reduces cell division?
Methotrexate works by inhibiting DNA synthesis and cell replication by competitively inhibiting the conversion of folic acid to folinic acid.
There are about 5 different reasons why a person may have gout. What are the differences between these mechanistic alterations to the body that lead to gout?
- Increase PRPP synthase
- Increase PRPP aminotransferase (1 and 2: resistance to feedback inhibition, resulting in overproduction and over-excretion of uric acid)
- Decrease HGPRT (partial activity) - decrease HGPRT blocks the conversion of hypoxanthine to IMP, the hypoxanthine increase—-> xanthine increase—>uric acid increase.
- glucose-6-phosphatase activity, this enzyme is the last pathway of gluconeogenesis and is aim to convert glucose 6 phosphate into glucose, when this enzyme activity is low, it will ends up with glucose-6-phosphate and enter pentose phosphate pathway. The end product of PPP is ribose-5-phosphate, which is the first synthesis of nucleic acid synthesis. The more ribose 5 phosphate we have, it will override the feedback inhibition, massive amount of ribose-5-phosphate will trigger PRPP synathase, which backs to and accelerate purine synthesis. The more purine degraded will end up with more AMP and GMP—-increase uric acid—gout.
- Kidney function decreases due to age, kidney impaired.-NOT biochemical
Because of Colchicine’s mechanisms of action – what adverse effects are inevitable as the dose increases or the drug is given for long periods of time?
The primary action of colchicine is anti-mitotic, which inhibit cell mitosis by binding to the protein tubulin and preventing depolarisation into the microtubules.
- Loss of fibrilla tubules in granulocytes can inhibit neutrophil migration, chemotaxis, adhesion and phagocytosis in inflamed area. Secondary action is decrease mast cell histamine release.
- Because colchicine is well-absorbed after oral administration, it’s actively secreted into the bile (approximately 80% biliary clearance) and intestine and undergoes enterohepatic recirculation.
- Colchicine inhibits strong protein binding and is eliminated slowly, GI tract problem such as diarrhoea is inevitable as the dose increase or the drug is given for a long period of time
Compare and contrast the mechanisms of action of allopurinol and probenecid. (also explain the dose dependent paradoxical effect of probenecid).
- Allopurinol is a strong xanthine oxidase inhibitor which reduces the synthesis of uric acid and thus decreases the concentration of urine to below solubility
- Hypoxanthine reused through salvage pathway and indirectly reduced PRPP level.
- Probenecid increases renal excretion by block its renal tubular reabsorption. Reduces the renal tubular excretion of some acidic drugs(eg penicillin) cause their plasma concentration to rise and prolong their duration of action
Rasburicase works on uric acid, yet is not used for GOUT. What is its exact mechanism of action? What is it used for? What by-product of its reaction (given that it is an enzyme) can cause significant adverse effects, and why do you think it is not used for GOUT treatment?
- It can be used to convert uric acid to allantoin (water-soluble) via urate oxidase enzyme. Allantoin is more water soluble than uric acid and less precipitate in the renal tubules.
- Since rasburicase is an enzyme, cannot take this drug orally so it has to be done in IV fusion (Infused over 30min) to reduce effect of release uric acid when tumor (cancer) treated with chemotherapy or prophylactically for cancer therapy.
- By-product of this reaction is H2O2, causing hemolytic anemia.
- Not used for gout is because it also has another serious adverse effect such as acute kidney failure, anaphylaxis.
What is a key difference between Lesch Nyhan Syndrome and Gout give they can both work on the same enzyme (Salvage pathways)
Lesch Nyhan syndrome is more severe than gout, since it has completely loss of HGPRT activity.
-Gout still has some activity of HGPRT –> partial activity
