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34 Cards in this Set

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Which carbons on the purine ring can be oxidized and what does their respective oxidation lead to the formation of?
C6 gets oxidized first to make hypoxanthine.

Then C2 gets oxidized to make Xanthine.

Finally C8 gets oxidized to make Uric Acid
Hypoxanthine is the same oxidation state as
Adenine
Xanthine is the same oxidation state as
Guanine
what is the starting material for the synthesis of purines? What happens to it?
Ribose-5-phosphate. Reacted with ATP and PRPP Synthetase to make PRPP. 2 P's from ATP transfer making another end product AMP (not ADP).
What happens to the PRPP?
It reacts with AMIDO TRANSFERASE to make 5-phosphoribosyl-1-amine. This is the irreversible, commited step, and major control point for the pathway. Once this step is complete, then purine synthesis is destined
what happens to the 5-phosphoribosyl-1-amine?
it goes through 9 steps to make IMP, thus ending the de novo synthetic pathway
What regulates Amido Transferase
IMP AMP GMP
In the rest of the 9 steps, where do all of the nitrogens of the ring come from?
2 are donated by glutamine.
1 is donated by glycine
1 is donated by aspartate
In the rest of the 9 steps, where do all of the carbons of the ring come from?
2 are donated by glycine
1 by CO2 and 2 by folate
What does IMP make and how
IMP makes AMP via aspartate and GTP and synthetase

IMP makes GMP via glutamine (donates N's) and ATP and deHase. The dehase changes the IMP into the xanthine derivative, XMP before being changed to GMP
Nucleotide-5-phosphate kinases: specificity? R/IR? E source, rxn?
there are many of these kinases, a family of them. each of them are base specific but not sugar specific (can be deoxyribose or ribose). However, ie GMP kinase will only work if G is in molecule.
They are reversible and use ATP for E.

NMP + ATP --> NDP + ADP
Nucleotide-5-diphosphate kinases: specificity? R/IR? E source, rxn?
There is only one of these and it is not base specific or sugar specific. It will take G T U A or C. Uses ATP and is reversible. The only diphosphate that doesnt use this is ADP.

NDP + ATP --> NTP + ADP
The catabolism of Purine Nucleotides includes the removal of what 3 things followed by what?
removal of the amino group, phosphate, and sugar from the nitrogenous base followed by the oxidation of the base to uric acid by Xanthine oxidase. Need to strip those 3 things off GMP and AMP to turn it into uric acid.
How are those 3 things stripped off of GMP and AMP to make uric acid: AMP pathway
AMP --> IMP via deaminase THEN IMP --> Inosine via Phosphodiesterase

OR

AMP --> Adenosine via Phosphodiesterase THEN Adenosine --> Inosine via Deaminase

This inosine then turns into Hypoxanthine via Purine nucleotide Phosphorylase (takes off ribose/sugar)
How are those 3 things stripped off of GMP and AMP to make uric acid: GMP pathway
GMP --> Guanosine via Phosphodiesterase THEN Guanosine --> Guanine via Purine Nucleotide Phosphorylase then Guanine --> Xanthine via Deaminase
What happens to the hypoxanthine and xanthine
recall that hypoxanthine-->xanthine-->uric acid vvia Xanthine Oxidase, which is also a flavoprotein
Uric acid is converted to what? What is so special about this new product?
Sodium Urate - it is a unique salt b/c it has limited solubility. It is water soluble but has limited solubility. Doesn't take a lot of it to get to the point where no more will dissolve in solution.
Increase in what leads to Gout?
Uric Acid concentration in the urine.
primary gout vs. secondary gout.
primary gout is the genetic form. IMP is overproduced. Can also be a problem in terms of getting rid of uric acid.

in secondary gout, the gout is secondary to another disease. there is a high turnover rate of tissues.
How it gout treated?
Allopurinol is an inhibitor of Xanthine Oxidase. Inhibition of it will cut down on uric acid production. This leads to a result in increased levels of xanthine and hypoxanthine, which are more soluble than uric acid, therefore more easily excreted in the urine.
Allopurinol is a structural isomer of hypoxanthine. It has a similar structure by the N in the 7th position of hypoxanthine is moved to the 8th position on allopurinol.
What are the 2 purine salvage enzymes and what do they do?
HGPRT converts Hypoxanthine to IMP by using PRPP. It can also convert Guanine to GMP by using PRPP.

APRT converts Adenine to AMP by using PRPP

HGPRT is more active than APRT since it can yield AMP through production of IMP
Lesch-Nyhan Syndrome
genetic defect in HGPRT. These infants are very aggresive and try to self-mutilate themselves by chewing into their tissues with their teeth.
SCID
Defects in ADA --> Increase in adenosine and deoxyadenosine --> increase in dATP --> negatively modulated ribonucleotide reductase --> decrease in deoxynucleotide production --> impairs DNA synthesis --> prevents B and T cells from maturing properly --> immunodeficiency
Pyrimidine Nucleotide Biosynthesis - What is made first and then what is added? What are the 2 starting compounds? What is the end product?What is the rate limiting step and major control point?
The ring is made first and the ribose-5-P is then added (opposite of purines)

The two starting compounds are carbamoyl-P and Aspartate

THe end product is UMP

THe first step, using ASPARTATE TRANSCARBAMOYLASE, is the rate limiting step and major control point, irreversible
Where does the nitrogen of carbamoyl-P come from and how is carbamoyl-P made?
Glutamine donates the N.

compound is made via CP Synthetase II and ATP (not 2 here, just 1)
If the UMP cannot be made, then build up of...
ORATIC ACID (seen in urine). Therefore cannot make C, T, DNA, cells won't divide. Child will have anemia
What does UMP go on to make?
UMP ---> UDP ---> UTP ----> CTP via CTP Synthetase + Gln + ATP
What is the major control of that pathway?
CTP b/c it feeds back on the Aspartic Transcarbamoylase.
What are the positive and negative modulators for Aspartic Transcarbamoylase?
ATP is +
CTP is -
How are deoxynucleotides synthesized?
the enzyme RIBONUCLEOTIDE REDUCTASE takes the ribonucleotide diphosphate and reduces the second carbon on it to make the deoxynucleotide. The enzyme uses thioredoxin reductase. The substrates for the enzyme are UDP, CDP, GDP, and ADP
How is RIBONUCLEOTIDE REDUCTASE controlled?
has enormous amount of control mechanisms on it. It has multiple binding sites for allosteric regulators which can influence dNT production. Very imp b/c DdNT can only be used for DNA synthesis and serve no other purpose.
How is Thymidylate synthesized then?
dUMP is the only way to make dTMP. Enzyme is Thymidylate Synthase and a one carbon moiety is added from the folate pool. The reducing equivs are supplied by fH4 which is oxidized to FH2.
BIG PICTURE
make UMP from de novo synthesis --> UDP --> UTP --> CTP --> UTP and CTP are used for energy to make RNA --> UDP and CDP that are generated while making RNA can be converted to deoxy form --> dUDP is rapidly converted to dUMP --> dTMP
What compounds do ribonucleotide reductase and dinucleotide kinase give?
ribonucleotide reductase give the deoxydiphosphates

dinucleotide kinase give the deoxytriphosphates. Without these, no DNA replication --> no cell division.