Nucleotides & Folate Flashcards
Name 5 functions/derivatives of nucleotides
-Building blocks of DNA/RNA
-Biological energy transduction (ATP,GTP)
-Coenzymes (NAD, FAD, CoA)
-Signal transduction (cAMP)
-Carriers of activated intermediates (UDP-Glc)
What are the 3 components of nucleotides?
-Nitrogenous base
-Pentose
-Phosphate
What are the two types of nitrogenous bases? what are they?
Purines: adenine, guanine
Pyrimidines: Uracil, thymine, cytosine
What is a nucleoside?
nitrogenous base linked to a sugar by an N-glycosidic bond
What is the difference between an adenosine and a deoxyadenosine?
An adenosine is when the adenine of a nitrogenous base is linked to a ribose, the same is true for a deoxyadenosine except it is linked to a deoxyribose
How are nucleotides and nucleosides related?
a nucleotide is a phosphorylated nucleoside
What is CoA synthesized from?
cysteine, pantothenic acid, and ATP
What is the function of FAD & NAD+?
they are coenzymes in redox rxns
What is the function of S-Adenosyl Methionine (sAME)
it functions in methyl transfer rxns
What is the function of cAMP and cGMP?
they are second messengers and intracellular signal transducers
How are nucleotides linked in DNA/RNA?
they are linked 3’-5’ phosphodiester bonds catalyzed by polymersases
What are the two ways to make purines?
-De Novo
-Recycling
What are the 4 main components of purines?
-Aspartate
-Glycine
-2 forms of folate
-Glutamine
Describe de novo purine synthesis
-ribose 5-phosphate - PRPP via PRPP synthase
- requires ATP
-10 steps (we dont need to know)
- Then the first ring is formed (using glycine, THF, glutamine, requires ATP)
-Formation of the second ring (using folate and aspartate) yields IMP
-IMP is converted to AMP and GMP
Where are 3 steps you can regulate purine synthesis?
-PRPP synthase (inhibited by products)
-Adenylosuccinate synthase (negative feedback by AMP)
-IMP dehydrogenase (G branch: negative feedback by GMP)
What are the 3 main components of pyrimidines?
Aspartate, glutamine, folate derivatives
What is the main difference between purine and pyrimidine synthesis?
in pyrimidine synthesis the ring is formed BEFORE the sugar (PRPP) is added
Describe the de novo synthesis of pyrimidines
-Glutamine + ATP +CO2 -> carbamoyl phosphate via carbamoyl phosphate synthetase 2
-CPS + glutamate + aspartate +… -> DHOA
- DHOA + PRPP (many steps later) -> UDP which can be converted to either TMP of UTP/CTP
What is the difference between carbamoyl phosphate synthetase 1 & 2 ?
CPS 1: liver mitochondria, urea cycle, nitrogen source is NH4
CPS 2: cytosol of many cells, pyrimidine biosynthesis, nitrogen sources is glutamine
What is the nitrogen source of CPS 2?
Glutamine
How would you regulate pyrimidine synthesis?
stimulate/inhibit CPS2
inhibit: UTP (product)
stimulate: PRPP and ATP (reactants)
What is the methyl donor to form dTMP from UDP?
folate derivative N5,N10-methylene tetrahyrolate
What enzyme is used to convert dUMP to dTMP?
thymidylate synthase
What critical biological process requires thymidylate synthase?
DNA replication
Why is thymidylate synthase a target of chemotherapy drugs?
you can use inhibitors of thymidylate synthase to block DNA replication of rapidly growing cells
True/False: breakdown of DNA and RNA is a continuous cell process
True
What is dietary DNA/RNA digested in to?
oligonucleotides, nucleotides, free bases
What are the turnover two fates of purine and pyrimidine nucleosides?
-degraded to waste products
-salvages to reform nucleotides
What are the fates of pyrimidine catabolism?
-Cytosine & Uracil: converted to beta-alanine -> acetyl CoA which can enter the TCA cycle
-Thymine: converted to beta aminoisobutyric acid -> succinyl CoA which can enter the TCA cycle
NH3 and CO2 are also formed which enter the urea cycle
Describe the salvage of pyrimidine bases
-Uracil + ribose-1-P -> UMP via uridine phosphorylase
-Thymine + deoxyribose-1-P to form TMP via thymidine phosphorylase
Describe purine catabolism
adenosine and guanosine are both converted to xanthine which is converted to uric acid via xanthine oxidase
how is uric acid excreted by different species?
great apes and Dalmatians excrete uric acid but other mammals concert uric acid to allantoin via uric oxidase
What enzyme converts uric acid to allantoin?
urate oxidase
What enzyme converts xanthine to uric acid?
xanthine oxidase
From what does xanthine originate?
adenosone or guanosine
Why don’t great apes and humans just convert uric acid to allantoin which is more water soluble than uric acid?
they have accumulated mutations that result in a non functional urate oxidase
True/False: uric acid is more water soluble than allantoin
false
What happens when serum urate levels exceed the solubility limit?
crystals form in soft tissues and joints, kidney stones can form
Why do dalmatians have higher levels of uric acid in blood and urine?
They are homozygous for the mutation in the SLC2A9 gene which leads to a defect in the ability to transport uric acid into hepatocytes for excretion
What is a common medical problem of dalmatians caused by their method of uric acid excretion?
urinary tract stones
How can you manage/prevent uroliths?
avoid high purine foods, increase hydration, rx diets, medications such as allopurinol
How does allopurinol work? what is it a tx for?
it is a competitive inhibiter of xanthine oxidase which prevents the formation of uric acid. Helps prevent urinary stones in dalmatians
What are two ways to salvage purine bases?
-purine phosphoribosylation by PRPP to form a purine 5 mononucleotide (aka AMP, IMP, GMP)
-phosphoryl transfer from ATP to a purine ribonucleoside
What vitamin is folic acid?
vit B 9
Can animal synthesize folic acid?
no, it is synthesized by bacteria
What must happen to folic acid before it can be absorbed?
dietary folic acid is typically polyglutamated, so glutamates are removed prior to absorption
Where is folic acid absorbed?
proximal small intestine
What occurs to “activate” folic acid into its derivatives?
- reduced to dihydrofolate and then to tetrahydrofolate via folic acid reductase
What amino acid provides the methylene group to form N5, N10 methylene folate?
serine
List 4 biological roles of folic acid
-One carbon metabolism
-dTMP synthesis
-Purine biosynthesis
-DNA methylation
What vitamin provides a methyl group for DNA methylation?
folate
Why would megaloblastic anemia be a result of folate deficiency?
because it results in the inhibition of DNA synthesis during red blood cell production, so you have continued growth without division
