(L8) Nucleotide Metabolism Flashcards
What are the purines and pyrimidines?
L8 S4 LO1
Purines (two-membered ring):
- adenine
- guanine
Pyrimidine (one-membered ring):
- cytosine
- uracil
- thymine
Differentiate between nucleotides and nucleosides.
L8 S4 LO1
Nucleoside:
- nitrogenous base
- sugar
Nucleotide
- nitrogenous base
- sugar
- phosphate
What is the energy in the bonds between each phosphate in a nucleotide?
L8 S7 LO1
ATP -> ADP + Pi -7.3kcal/mol
ATP -> AMP + PPi -10.9kcal/mol
PPi -> Pi + Pi -4.0kcal/mol
What cofactors are derived from nucleotides?
L8 S9 LO1
- CoA
- FAD
- FMN
- NADPH
- NADH
What are the atom sources of purine rings?
L8 S218 LO2
- Aspartate
- CO2
- Glutamine
- Glycine
- N10-formyl-tetrahydrofolate
What are the steps of purine synthesis?
L8 S18 LO2
- activation of ribose 5-phosphate to PRPP
- addition of amine to PRPP
- production of IMP
- conversion of IMP to AMP or GMP
Sugar is made first
What is the rate limiting step of purine synthesis?
L8 S20 LO2
Glutamine:phosphoribosyl pyrophosphate amidotransferase
PRPP -> PRA
How is purine synthesis regulated?
L8 S23 LO2
PRPP production and conversion is inhibited by IMP, AMP, and GMP (if you have them you don’t need more)
AMP and GMP are inhibited by themselves (if you have enough of one you don’t need more of it, you need more of the other)
Conversly, AMP and GMP produciton are stimualted by the other (if you have enough of one, you need more of the other)
What noteworthy features are there about the conversion of IMP to either ATP or GTP?
L8 S22 LO2
ATP:
- uses GTP for energy
- regenerates fumarate (TCA)
- goes through adenyloxuccinate intermediate
GTP:
-uses ATP for enery
- uses NAD+
- goes through XMP intermeidate
What are the atom sources of pyrimadine rings?
L8 S24 LO2
- Carbamoyl phosphate
- Aspartate
What are the steps of pyrimidine synthesis?
L8 S24 LO2
- pyrimidine ring formation as orotate
- attachment of orotate to PRPP making UMP
- conversion of of UMP to TMP or CMP
Ring is made first
Which nucleotides require folate derivatives to be synthesized?
L8 S21; 27 LO2
- IMP
- ATP (IMP derivative)
- GTP (IMP derivative)
- TTP
What is the rate limiting step of pyrimidine formation?
L8 S25 LO8
Carbamoyl phosphate synthetase II
What is the purpose of the dUDP loop in pyrimidine synthesis?
L8 S27 LO2
Keeps dUTP level low to prevent it from being incorporated into DNA
What are the inhibitory step of pyrimidine synthesis?
L8 S28 LO2
Carbamoyl phosphate:
- inhibited by UMP/UTP
- stimulated by PRPP
Aspartate transcarbamoylae:
-inhibited by CTP
What is methotrexate and what is it used for?
L8 S31 LO2
Structurally similar to folic acid.
Tightly binds dihydrofolate reductase which inhibits ATP, GTP, and TTP production.
This is used to kill rapidly dividing cells, such as cancer.
What are sulfa drugs and what are they used for?
L8 S32
Antibacterial that inhibtis bacterial DNA replicaion by inhibiting enzyme that incorperates p-aminobenzoic acid (PABA) into folate
Does not affect humans as we do not synthesize folate
What is acyclovir and what is it used for?
L8 S33 LO2
Antiviral which targes viral thymidine kinase causes it to be phosphorylated.
When incorperated into viral DNA, it terminates transrciption due to lack of 3’ OH
How are purines catabolized?
L8 S35 LO3
GMP and AMP are both converted into xanthine which is then converted into uric acid.
What is SCID?
L8 S38 LO3
Severe combined immunodeficiency
Deficiency of ADA from adenine degradation pathway which lead to build of of dATP which inhibits formation of other dNTPs.
Results in compromise in both T and B cells leading to severe immune deficiecny.
Most commonly affects males as the most common form is X-linked
What is gout?
L8 S39 LO3
Caused by crystaliztion of excess uric acid, most commonly in toes, which can cause extreme pain.
Uric acid is produced during purine degrataion by xanthine oxidase
How are pyrimidines catabolized?
L8 S40 LO3
Converted to malonyl CoA:
- uracil
- cytosine
Converted to methylmalonyl CoA or succinyl CoA:
-thymine
What are the main nucleotide salvage pathways?
L8 S42 LO4
AMP:
-adenine phosphoribosyltransferase (APRT)
GMP and IMP:
-hypoxanthine-guanine phosphoribosyltransferase (HGPRT)
What is Lesch-Nyhan syndrome?
L8 S43 LO4
Results from <1.5% normal HGPRT activity (GMP/IMP salvage pathway) resulting in hyperuricemia.
Clinical features:
-self-mutilation
- poor muscle control
- MR
Gout like features can be lessend by allopurinal treatment
What is acheived by inhibiting GMP and dGTP production and how is it done?
L8 S33
Doing so especially effects lymphocytes, limiting their replicaiton.
This can be used as an immuosuppresant to prevent transplant rejection.
It is done by targeting IMP dehydrogenase (IMP -> XMP)
