lecture 6 Flashcards
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
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))
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
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
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
what sugar does RNA use
ribose
what sugar does DNA use
deoxyribose
pyrimidine
1 ring
uracil
cytosine
thymine
purine
2 rings
adenine
guanine
Pure As Gold
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
what sugar does DNA use
deoxyribose
no ribose
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
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
AMP is
adenine with ribose-P added
IMP turns into adenylosuccinate then AMP (adenylate)
GMP is
guanine with ribose-P added
IMP (inosinate) turns into Xanthylate then GMP(guanylate)
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
explain Adenine Phosphoribosyl transferase
used when purine comes off sugar
PRPP + Adenine = Adenylate + PPi
explain hypoxanthine-guanine phosphoribinosyl transferase
used when purine comes off sugar
PRPP + guanine = guanylate + PPi
PRPP + hypoxanthine= inosinate (IMP)+ PPi
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
