lecture 6 Flashcards by jillian Bastidas

your patient shows retarded growth, severe anemia and high levels of orotic acid in their urine (orotic aciduria)
Cause
Treatment

high orotate (one of the products/steps of pyrimidine production)

means either
oroate
-orotate phosphoribosyl transferase 
=orotidylate
or 
orotidylate
-orotidylate decarboxylase
UMP( uridylate)
is NOT working

Treatment: feed them pyrimidine (uridine triacetate UTP)

if body has pyrimidines then it doesn’t need to make pyrimidine therefore the step/products will not be produced and therefore no buildup can happen
end products feedback inhibit production of pyrimidines

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canine with lymphoma
is 5-flurouracil good option?
if not what is a good option?

5-FU is toxic for dogs
-gastro(hypersalivation, vomiting), CNS (ataxia, seuzures) and bone marrow suppression (anemia)

Treatment: Use aminopterin (methotrexate)

-inhibits dihydrofolate reductase (dihydrofolate to tetrahydrofolate which turns into Methylenetretrahydrofolate (dUMP to dTMP))

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called to zoo for animal with uric acid in urine and in pain
Which animal?
Treatment?

primate- uric acid is end product of purine degradation

treatment: ALLOPURINOL
competitive inhibitor for xanthine oxidase (enzyme used in purine deg)-
allopurinol gets attached to PRPP, lowers level of PRPP, which in turn lowers the production of biosynthesis

stops hypoxanthine from changing into xanthine
stops xanthine from turning into uric acid

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dalmatian with blood in urine

dalmatians have defect in liver and can not take up uric acid into liver to be converted into allantoin, therefore they can have build up in uric acid which can lead to gout.

gout can be treated will ALLOPURINOL

blocks Xanthine oxidase
uric acid is form breakdown of purines

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treatment for leshmaniasis?

parasite that feeds on purine from host. if you use ALLOPURINOL to reduce the amount of purines the host make, hopefully starving the parasite

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what sugar does RNA use

ribose

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what sugar does DNA use

deoxyribose

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pyrimidine

1 ring
uracil
cytosine
thymine

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purine

2 rings
adenine
guanine

Pure As Gold

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what is committed step to make purine

PRPP
5-phosphoribosyl-1-pyrophosphate

amidoposphoribosyl transferase
(2 phospate gets switch into amino group) (+glutamine --> glutamate)

5-phosphoribosyl-1-amine and PPi

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what sugar does DNA use

deoxyribose

no ribose

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how to make purine

ribose 5 phosphate

add ATP (ribose phosphate pyrophosphokinase) 2 phosphate gets added)

PRPP (5-phosphoribosyl-1-pyrophosphate)

add glutamine (2 phospate gets switched with amino group)
-amidophosphoribosyl transferase (committed step_

5-phosphoribosyl-1- amine
and PPi

bunch of steps

get purine inosinate (IMP)

inosinate (IMP) can turn into

-adenylosuccinate then ADENYLATE (AMP)
or
-xanthylate then GUANYLATE(GMP)

AMP is adenine with ribose-P added

GMP is guanine with ribose-P added

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what is committed step to make purine

PRPP

amidoposphoribosyl transferase
(2 phospate gets switch into amino group) (+glutamine --->glutamate)

5-phosphoribosyl-1-amine and PPi

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AMP is

adenine with ribose-P added

IMP turns into adenylosuccinate then AMP (adenylate)

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GMP is

guanine with ribose-P added

IMP (inosinate) turns into Xanthylate then GMP(guanylate)

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how to fix when purine rings come off sugar

hypoxanthine-guanine phosphoribinosyl transferase

PRPP + guanine = guanylate (GMP) + PPi

PRPP + hypoxanthine= inosinate (IMP)+ PPi

Adenine Phosphoribosyl transferase
PRPP + Adenine = Adenylate(AMP) + PPi

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explain Adenine Phosphoribosyl transferase

used when purine comes off sugar

PRPP + Adenine = Adenylate + PPi

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explain hypoxanthine-guanine phosphoribinosyl transferase

used when purine comes off sugar

PRPP + guanine = guanylate + PPi

PRPP + hypoxanthine= inosinate (IMP)+ PPi

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lesch-nyhan syndrome

what is a common symptom

deficiency in HGPRT

self mutilation

body cant fix when purines come off PRPP/sugar therefore there is more PRPP just floating around in the body.

PRPP causes increase in purine biosynthesis (increased purine biosynthesis).

too many purines need to be broken down. breakdown of purines creates uric acid.

how to degrade purines in humans and primates

AMP
-adenosine deaminase
IMP
-gets changed into
Hypoxanthine
-Xanthine Oxidase
Xanthine
-Xanthine Oxidase (again)
Uric acid

how does adenosine deaminase change AMP

AMP changes into IMP

purine degradation part 1

AMP (adenylate) (adenine with ribose-P) (one of the products of purine synthesis)

NH2 gets switched into double bonded O

this is IMP (inosinate)

how does xanthine oxidase change hypoxanthine

Hypoxanthine turns into Xanthine

purine degradation part 3

H turned into double bonded O

(oxidase means lose electron- reaction is reduced) (LEO) makes it more water soluble by added O

this is now Xanthine

how does xanthine oxidase change Xanthine

Xanthine turns into Uric Acid

purine degradation part 4

H turned into double bonded O

(oxidase means lose electron- reaction is reduced) (LEO)- makes it more water soluble by added O

this is now Uric Acid

defect in adenosine deaminase

enzyme for purine degradation part 1 AMP to IMP

no adenosine deaminase means no immune system (bubble boy)

purine degradation in other animals

``` (1st 4 steps the same) AMP -adenosine deaminase IMP -gets changed into Hypoxanthine -Xanthine Oxidase Xanthine -Xanthine Oxidase (again) Uric acid ``` non primate mammals will go one step further uric acid gets changed into allantoin allantoin allantoate urea and glyoxylate (fish) 4NH4 and 2 CO2 (marine invertebrates)

end product of purine degradation for non primate mammals

allantoin uric acid + O2= allantoin

end product of purine degradation for fish

urea and glyoxylate allantoin + water= allantoate allantoate +water=urea and glyoxylate

end product of purine degradation for marine invertebrates

4NH4 and 2 CO2 urea plus water = 4NH4 and 2 CO2

disease from too much uric acid

gout

how does allopurinol work

competitive inhibitor for xanthine oxidase( step 3 and 4 of purine degradation) - stops hypoxanthine from changing into xanthine - stops xanthine from turning into uric acid allopurinol attaches to PRPP, this means there is less free PRPP floating around, this means purine biosynthesis goes down decrease in purine synthesis means there is not extra purines that need to get broken down. therefore uric acid is not being produced

problems with allopurinol

allopurinol blocks xanthine oxidase meaning there can be a build up of xanthine (step from purine degradation). this buildup can be toxic

Xanthine oxidase deficiency treatment?

do not have enough xanthine oxidase (enzyme used in step 3 and 4 of purine degradation) patient cant break down xanthine leads to - xanthinuria - nephropathy - renal failure treatment: low purine diet and fluids

** your patient is suffering from gout-like symptoms. what treatment do you recommend? what is this treatment effective

allopurinol competitive inhibitor for xanthine oxidase thus decreasing the production of uric acid also binds to PRPP thus lowering the amount of purine synthesis. since high PRPP levels activate purine synthesis

*** will elevated PRPP levels increase or decrease purine biosynthesis

increase PRPP is first step of purine biosynthesis, would push the reaction forward

fetal death in dairy cows can be cause by errors in ____

``` pyrimidine metabolism (DUMPS) deficiency of uridine monophosphate synthase ```

pyrimidine biosynthesis

CO2 +glutamine + ATP -carbomoyl phosphate synthetase carbamoyl phosphate and aspartate - aspartate transcarbamoylase (removes Pi) - bunch of steps OROTATE -orotate phophoribosyl transferase (add orotate to PRPP) OROTIDYLATE -oritidylate decarboxylase (carboxyl group removed) Uridylate (UMP) (pyrimidine!!) UMP -nucleoside kinase= UTP (uridine triphosphate) UTP -glutamine= CTP (cytidine triphosphate) UTP inhibits aspartate transcarbamoylase(2nd step) and carbamoyl phosphate synthetase (1st step)

how to go from UMP to dTMP

UMP -ribonucleotide reducatase dUMP dUMP+ N5N10 methylenetetrahydrofolate -thymidylate synthase dTMP and Dihydrofolate TO GO BACKWARDS Dihydrofolate -dihydrofolate reductase N5N10 methylenetetrahydrofolate

UMP can change into

UMP- nucleoside kinase=UTP -glutamine=CTP UMP- dUMP-dTMP

how do you prevent thymidine production

inhibit dihydrofolate reductase or inhibit thymidylate sunthase (pyrimidine synthesis) dUMP to dTMP

inhibition of thymidine production is a common way chemo works by

preventing production of thymidine which kills cell fluorouracil inhibits -thymidylate synthase (dUMP to dTMP) aminopterin (methotrextate) inhibits dihydrofolate reducatse (dihydrofolate-methylenetetrahydrofolate)

how is thymidylate synthase inhibited

fluorouracil | stops dUMP into DTMP

how is dihydrofolate reductase inhibited

aminopterin and amethopterin (methotrexate) stops dihydrofolate back into Methylenetetrahydrofolate

what species can 5-flurorouracil be used

cats- but very careful with dosage

*** in class we discussed two compounds that inhibit production of dTMP. What are these compounds and what specifically do they inhibit?

Fluorouracil -inhibits thymidylate synthase (dUMP into dTMP) Methotrexate(aminopterin) - inhibits dihydrofolate reductase (dihydrofolate back into methlenetetrahydrofolate)

Pyrimidine synthesis

G(CPS)A(AT)--- Oroate (OPT)=Orotidylate(OD) =UMP ``` Ump Uridylate 1.UMP 2. UMP-> UTP 3 UMP-> UTP-> CTP 4.UMP (RR) dUMP dUMP + tetra (TS) -> dTMP + dihydrofolate ``` (go backwards) dihydrofolate (DR) =tetra

what is a feedback inhibitor of the pyrimidine synthesis and which step does it work?

UTP (uridine triphospate) blocks step 1 glutamine +CO2 + ATP (CPS) = CP + Aspartate step2 aspartate (AT) = bunch of steps orotate