Nucleotide Metabolism Flashcards
TMP is formed from dUMP by addition of ____
5,10-methylene-FH4 (THF)
High inorganic phosphate levels indicates low _____ levels
nucleotide
What is a good treatment for hereditary orotic urinemia?
- Uridine; Forms UTP (salvage pathway) that then goes to form CTP
** UTP also inhibits CSP II that then goes to reduce the levels of orotic acid that are formed de novo
Arts Syndrome is an x-linked genetic disorder in what enzyme?
- PRPP synthetase
About what % of nucleotides come from the diet in humans?
- 5%; most RNA and DNA in the diet are degraded and excreted
A deficiency in purine nucleoside phosphorylase causes what kind of immunodeficiency?
T-cell
** Nucleoside accumulate and the increase in dGTP and decrease in GMP may contribute to the symptoms and be toxic to lymphocytes
Leflunomide blocks orotate production in the ______ formation pathway
pyrimidine
CTP synthetase + glutamine takes UTP and forms ____
CTP
Pyrimethamine is used in the treatment of ____ and is derived from purines
Malaria
Gout occurs when there are [high/low] levels of uric acid in the blood
-high
If have a deficiency in adenosine deaminase (ADA), then what condition would you have?
SCID
When making purines de novo, what do you start with to make nucleotides?
Glucose
Folic acid = Vit ___
B9
In the guanosine (nucleoside) interconversion pathway, ribose 1-phosphate is lost and guanine (free base) is formed using what enzyme?
- Purine nucleoside phosphorylase
In purine degradation, nucleic acids are turned into free bases and then into _____ that then turns into uric acid that is excreted in the urine
Xanthine
The inactive form of glutamine phosphoribosyl amidotransferase is a _____ and the active form is dimerized by the increase in ____ levels
Dimer; IMP, GMP, AMP
Methotrexate inhibits ____ and this drug is useful in the treatment of some cancers by slowing down DNA synthesis
DHFR
6- Mercaptopurine inhibits _____ synthesis
Purine
In over 90% of cases, gout is caused by an [overproduction/ underexcretion] of uric acid
Underexcretion
Aspartate + [Glutamine + CO2+ 2___]—> ____ _____ and this reaction uses the enzyme CPS-II
ATP; Carbamoyl phosphate
Increasing the levels of PRPP in some cases of gout leads to the increase activity of what rate-limiting enzyme?
- Glutamine phosphoribosyl amidotransferase
Ribonucleotide reductase requires the cofactor _____ and NADPH from the pentose phosphate pathway to reduce NDP to dNDP
- thioredoxin
Nucleotide salvage occurs mainly in the _____ and it is the process of buliding nucleotides from nucleosides and ____
Liver; bases
Trimethoprin (Septra) is used to treat _____ infections and is derived from ______
bacterial; purines
Where in the body is uric acid generated and then transported?
Liver and then to the kidneys
Position 1 (nitrogen) of nucleotides comes from ______
Aspartate
IMP forms _______ and then AMP. What is the energy source and the amino acid needed to form this intermediate?
Adenylosuccinate; GTP and aspartate
Hyperuricemia leads to what condition?
Gout
___ in the stomach degrades nucleic acids and ____ from the pancreas breaks the nucleotides down even more
Pepsin, nucleases
When adding a phosphate to ADP, GDP and others NDPs, what enzyme is needed and is it specific to the nucleosides?
Nucleoside diphosphate kinase; No
Allopurinol is used in the treatment of ____ and is derived from purines
Gout
Carbons 4,5 and nitrogen at 7 comes from ____ to build purines
Glycine
5-Fluorouracil is an anti-tumor drug that inhibits the enzyme thymidylate synthase that inihibits the conversion of dUMP to _____
dTMP
The salvage pathway is very _____ favorable
Energetically
Allopurinol is converted to ______ and that form is an irreversible inhibitor of ____ _____
oxypurinol; xanthine oxidase
von Gierke disease is a disease that is caused by a genetic deficiency in _______ that leads to glucose-6-phosphate being shunted into the pentose phosphate pathway that leads to production of __________ which eventually leads to hyperuricemia
- glucose 6-phosphatase; ribose 5-phosphate
Folate is converted to _____ by DHFR and requires NADPH and then converted to ______ by DHFR and requires NADPH and then a formyl group is added to the ___ position
Dihydrofolate; Tetrahydrofolate; 10th
Carbomoyl phosphate + _____ = Carbamoyl aspartate –> _____
asparate; orotic acid
Mutations in UMP synthase cause what hereditary disease that results in poor growth, anemia, and high levels of orotic acid in the urine?
-Hereditary orotic aciduria
IMP is converted to XMP and then ___ by what enzyme?
GMP; IMP dehydrogenase
Monosodium urate crystals in the _____ results in inflammatory response
joints
Hydroxyurea is used to treat leukemia and sickle cell anemia. Which enzyme does it inhibit and what does this cause?
Ribonucleotide reductase; causes reduced DNA synthesis due to the reduction in dNDPs
B-aminoisobutyrate and B-alanine are excreted in urine or converted to methylmalonyl-coA or malonyl-coA that are used in ____ ____ biosynthesis
fatty acid
Negative regulation of 5-phosphoribosyl 1- amine is even more inhibited when AMP is paired with ___ or ___ because there are two different regulatory sites and the combination is additive
IMP; GMP
Mecaptopurine is used to treat _____
Cancer
In pyrimidine degradation, cytosine is degraded to ____ and then that is degraded to B-alanine which is soluble
uracil
Positions 3 and 9 (nitrogens) of pyrimidines (and 3 of purines) comes from _____
Glutamine
IMP forms GTP by first forming the intermediate XMP. What is the energy source and the amino acid needed to form GTP from XMP?
ATP; Glutamine
When adding a phosphate to AMP and GMP, what type of enzymes are needed and are they specific to the nucleosides?
Kinase; yes
Ribose-5-phosphate + ATP is converted to _____ with what enzyme?
PRPP; PRPP synthetase
What is the goal of purine de novo synthesis?
To create ATP and GTP
Deficiency in ADA results in accumulation of ____ and high levels of this is toxic to lymphocytes
dATP
What enzyme converts ADP to dADP?
RR (ribonucleotide reductase)
In DNA, what constituent is at the 2’ carbon?
-H
What is necessary to combine with the free bases (adenine, hypoxanthine, guanine) in the purine salvage pathway to create nucleotides?
- PPRT
Mycophenolic acid inhibits what enzyme resulting in its property of immunosuppression?
IMP dehydrogenase
List the pyrimidines:
- Cytosine
- Uracil
- Thymine
** CUT the PY (pie)
Negative regulation of 5-phosphoribosyl 1- amine is very sensitive to levels of ____ because the Km is much lower showing a sigmoidal curve
PRPP
How many ways are there to produce dUMP?
2
THF carries __ carbon and that is added to the __ and ___ position on nucleotides (purines)
1 carbon; 2nd and 8th position
Nucleoside is a base + ____
sugar
In the purine salvage pathway, adenine is converted into AMP using what enzyme?
APRT
Orotic acid (Orotate) + ____ –> OMP –> UMP; all of these reactions are catalyzed by UMP synthase
PRPP
___ is much less stable than DNA
RNA
THF donates how many carbons to purine biosynthesis?
-2 carobons at position 2 and 8
What is the goal of pyrimidine de nove synthesis?
To create CTP, UTP, and TTP
Why would some cancer patients be treated with allopurinol or rasburicase?
Because during tumor cell lysis (via treatment with chem and cytotoxic drugs), nucleic acids are being released and they are being degraded and converted to uric acid, thus leading to hyperuricemia
If ___ is high then GMP/GTP is increased in the purine biosynthesis pathway
ATP
Nucleotide is a base + sugar + ____
Phosphate groups (mono, di, tri)
If ___ is high then AMP/ATP is increased in the purine biosynthesis pathway
GTP
Sequence of bulding purines
- Glycine (+ATP)
- THF (C2)
- Glutamine (+2ATP)
- CO2 (C6)
- Aspartate (+ATP)
- THF (C8)
** GTGCAT; “Got To Go CAT”
PRPP + glutamine forms ____________ with the use of what enzyme?
5-phosphoribosyl 1-amine; glutamine phosphoribosyl amidotransferase
AMP is converted to adenosine and then adenosine is converted to inosine. What enzyme converts adenosine to inosine?
- Adenosine deaminase
PRPP + ____ = nucleotide
** Catalyzed by either HGPRT (hypoxanthine and guanine) or APRT (adenine)
Base
What enzyme regulates the key step in pyrimidine biosynthesis?
CPS II
Uric acid overproduction may occur when which enzymes is increased that leads to incrased PRPP levels?
- PRPP synthetase
Allopurinol inhibits ____ oxidase and is a treatment for gout
xanthine
How does probenecid treat gout?
- By increasing the excretion of uric acid
Tetrahydrofolate is necesary to form dUMP. What drug inhibits dihydrofolate reductase?
Methotrexate
Ribonucleotide reductase has 2 allosteric sites: one controls activity and the other controls _____ specificity
substrate
Red blood cells and ______ use which pathway to create nucleotides?
- Salvage
High levels of dATP inhibits which enzyme that results in reduction in DNA synthesis
Ribonucleotide reductase (RR)
NDP is converted to dNDP by which enzyme?
Ribonucleotide reductase (RR)
Lesch Nyhan syndrome is an x-linked recessive disorder that causes a deficiency in HGPRT and that leads to increased levels of ____ and that drives which enzyme to make more 5-phosphoribosyl 1-amine leading to neurological problems and gout?
- PRPP; glutamine phosphoribosyl amidotransferase
In Arts Syndrome, there can be either a decrease or an increase in which enzyme?
- PRPP synthetase
In the pyrimidine salvage pathway, uracil or cytosine is converted to uridine or cytosine by adding ______. Thymine is converted to thymidine by adding ______.
Ribose 1-phosphate; Deoxyribose 1-phosphate
Through which pathway is ribose- 5- phosphate made?
- Pentose phosphate shunt
The creation of 5-phosphoribosyl 1-amine is a ____ step and is irreversible in purine biosynthesis
committed
AMP deaminase deficiency (AMP –> IMP) occurs in ____ and is often asymptomatic, but can lead to skeletal muscle myopathy and/or fatigue and cramps upon exercising
Muscle
Thymine is degraded to ______ in pyrimidine degradation
- B-aminoisobutyrate
Pyrimidine nucleotide degradation products are _______ while purine nucleotide degradation products are _______
Soluble; insoluble
Which organ is the primary producer of nucleotides?
- Liver
The active form of form of glutamine phosphoribosyl amidotransferase is a _______ and has increased activity with increased ____ levels
Monomer; PRPP
Azidothymidine (AZT) is used to treat ____ and is derived from purines
HIV
In forming pyrimidines, what occurs differently at the beginning?
Create the ring and then add the ribose and the phosphate
Hypoxanthine is inosine + _______
- ribose
List the purines and derivatives
Purines:
- Adenine
- Guanine
Derivatives
- Xanthine
- Hypoxanthine
- Uric acid
Inosine is a _______
nucleoside
Acyclovir is used in the treatment of _____ and is derived from ______
herpes; purines
Hypoxanthine is the base of ___
IMP
Azathioprine (AZA) is derived from _____ and used in organ transplantation
Purines (A,G)
Ribavirin is inhibits what IMP dehydrogenase and that inhibits ____ formation which makes it an effective anti-viral and anti-tumor drug
GMP
In RNA, what constituent is at the 2’ carbon?
-OH
Carbon 6 of purines and carbon 2 of pyrimidines comes from ___
CO2
Allopurinol treats gout by doing what?
-Inhibiting xanthine oxidase, which decreases the production of xanthine from hypoxanthine that then goes to form uric acid
Lesch-Nyhan Syndrome involves a deficiency in _______ that is a part of which pathway of purine biosynthesis?
HGPRT; salvage
Rasburicase is a recombinant form of what enzyme that is present in animals that converts uric acid into a soluble allantoin?
- Urate oxidase
Sulfa antibiotics inhibit ____ folic acid synthesis
Bacterial
In the purine salvage pathway, hypoxanthine and guanine are converted into IMP and GMP, respectively, using what enzyme?
HGPRT
