Nucleotide Metabolism Flashcards by Lily Nunvar

Carbon can be in different ____ states. ___ ___ has the most electrons and is the most reduced. ___ ___ is the most oxidized state.

Oxidation
Methyl carbon
Carbon dioxide

How well did you know this?

Not at all

Perfectly

___, ____, and _____ are three ‘one carbon’ donors aka ‘methyl donors’ that allow the body to perform reactions that shuffle ___ ___.

Folate, vitamin B12,
S-adenosylmethionine
Single carbons

How well did you know this?

Not at all

Perfectly

Deficiencies in either folate or vitamin B12 result in ____ ___ due to impaired ____ synthesis.

Macrocytic anemia
Nucleotide

How well did you know this?

Not at all

Perfectly

Carbons are donated to ____ at different oxidation states. Once bound to Tetrahydrofolate, the ____ state of the one carbon can be changed. After donating the one carbon for biosynthesis reactions, the ____ is regenerated.

Tetrahydrofolate
Oxidation
Tetrahydrofolate

How well did you know this?

Not at all

Perfectly

The vitamin precursor for the active cofactors is ____. It is abundant in green leafy vegetables, liver, legumes, yeast, and fortified flour. It has a _____ tail that is digested in the gut to _____.

Folate
Poly-glutamate
Mono-glutamate

How well did you know this?

Not at all

Perfectly

Folate is reduced to ____ _____ in the intestinal epithelial cells (this is the major form in the blood) and ____ in the liver.

N5-methyl Tetrahydrofolate
Poly-glutamate

How well did you know this?

Not at all

Perfectly

Proton coupled folate transporter (PCFT) is encoded on the ______ gene and expressed on enterocytes and hepatocytes

SCL46A1

How well did you know this?

Not at all

Perfectly

____ ____ ____: is an inherited mutation in the proton coupled folate transporter (PCFT) and causes functional folate deficiency despite adequate folate in the diet

Hereditary folate malabsorption

How well did you know this?

Not at all

Perfectly

Folate is reduced to ____ and reduced again to ____ by dihydrofolate reductase (DHFR)

Dihydrofolate (FH2)
Tetrahydrofolate (FH4)

How well did you know this?

Not at all

Perfectly

____ ____ is important for metabolism of dietary folate and for recycling oxidized folate to FH4. It is also an important drug target of ____ for cancer and rheumatoid Arthritis, ____ as an antibacterial, and ____ as an antimalarial.

Dihydrofolate reductase
Methotrexate
Trimethoprim
Pyrimethamine

How well did you know this?

Not at all

Perfectly

Once Tetrahydrofolate has been produced, it can take ___ ___ in different ___ states.

Single carbons
Oxidation

How well did you know this?

Not at all

Perfectly

Oxidation states of Tetrahydrofolate:

How well did you know this?

Not at all

Perfectly

Serine can donate a carbon through ____ _____ forming glycine and ______ FH4.

Serine hydroxymethyltransferase
N5N10-methylene

How well did you know this?

Not at all

Perfectly

The amino acid ___ is the most important contributor to the one carbon pool.

Serine

How well did you know this?

Not at all

Perfectly

Glycine can also donate carbon to Tetrahydrofolate through ___ ___ ___, forming _____FH4, NADH, NH4+, and CO2

Glycine cleavage enzyme
N5N10-methylene

How well did you know this?

Not at all

Perfectly

Serine, glycine, choline, histidine, and formate contribute to the ___ ___ ___.

One carbon pool

How well did you know this?

Not at all

Perfectly

Thymidine nucleotides, purine bases, methionine, and S-adenosyl methionine are _____ of the one carbon donations.

Products

How well did you know this?

Not at all

Perfectly

One carbon transfer in thymidine nucleotide synthesis:
The biosynthesis of ____ ____ from deoxyuridine monophosphate (dUMP) is a methylation reaction. The carbon donor is ____ ___, the carbon is in the ___ oxidation state. During the reaction, FH4 supplies electrons and oxidizes to ____, which then must be reduced to regenerate FH4.

Deoxythymidine monophosphate (TMP)
N5N10-methyl Tetrahydrofolate (FH4)
Methylene
Dihydrofolate (FH2)

How well did you know this?

Not at all

Perfectly

Thymidine nucleotide synthesis:
After N5N10-methylene TH4 donates a carbon to dUMP to for dTMP, it is left as _____. Dihydrofolate reductase (DHFR) must then use ____ oxidation to regenerate ____.

Dihydrofolate
NADPH
Tetrahydrofolate

How well did you know this?

Not at all

Perfectly

Thymidine nucleotide synthesis:
___ ____ reduces a methylene carbon to methyl during transfer to dUMP to make dTMP. Once FH2 is reduced by to FH4 via ____, it can then accept another one carbon group from ___ _____.

Thymidylate synthase (TS)
DHFR
Serine hydroxymethyltransferase

How well did you know this?

Not at all

Perfectly

____ (_____) is found in the diet in the meat, eggs, and dairy, either free or protein bound

Vitamin B12 (cobalamin)

How well did you know this?

Not at all

Perfectly

The ____ at the center of the ring in vitamin B12 can bind either a ____ group or an ____ ____.

Cobalt
Methyl
Adenine nucleotide

How well did you know this?

Not at all

Perfectly

N5-methyl TH4 can only donate it’s one carbon to ____ to form ____, which participates in only one reaction: donation of methyl to _____ to make ____.

Cobalamin
Methylcobalamin
Homocysteine
Methionine

How well did you know this?

Not at all

Perfectly

Adenosylcobalamin (5’-deoxyadenosylcobalamin) participates in only one reaction: catalyzes the isomerization of a methyl group in converting ____ ___ to ___ ___.

Methylmalonyl CoA
Succinyl CoA

How well did you know this?

Not at all

Perfectly

Vitamin B12 absorption and transport: Vitamin B12 first binds to ____ proteins secreted in the stomach. As this is digested, B12 binds ___ ___ (a protein). This complex is taken up by the intestinal epithelial cells and transported to the blood within ______ protein. Most of it is stored in the liver in complex with ____.

R-binder Intrinsic factor Transcobalamin II Cubillin

Vitamin B12 deficiency causes ___ ___: megaloblastic anemia plus neurological problems

Pernicious anemia

B12 deficiency can be dietary or the result of loss of function of ___ ___, _____, or ____.

Intrinsic factor, transcobalamin II, cubillin

Many causes of pernicious anemia are caused by ____ destruction of ____ ___.

Autoimmune Parietal cells

Vitamin B12 Reaction 1: Methylmalonyl CoA mutase rearranges the ___ ___ to form ___ ___, which can then enter the TCA cycle. Adenosyl cobalamin is not consumed in the reaction.

Carboxylic acid Succinyl CoA

Vitamin B12 Reaction 2: Methionine synthase catalyzes the transfer of methyl from ____ to ____ to make ____. Methylcobalamin is regenerated by accepting a methyl from fully reduced ____ ___.

Methylcobalamin Homocysteine Methionine N5-methyl TH4

Cells have a continuous cycle between methionine, S-adenosylmethionine (SAM), S-adenosyl homocysteine (SAH), and homocysteine. ____ is a methyl donor for many bio synthetic and regulatory enzymes, and it must be regenerated with ____ that comes from _____.

S-adenosylmethionine (SAM) Carbon N5-methyltetrahydrofolate

S-adenosylmethionine (SAM)

S-adenosylmethionine as a donor for bio synthetic regulatory enzymes:

Congenital Intrinsic factor deficiency can cause ____ ___. It is an inherited mutation in the gene encoding intrinsic factor.

Pernicious anemia

The methyl trap hypothesis: The only metabolic fate of N5-methyl TH4 is to lose its ____ to ____. In a dietary or functional deficiency of cobalamin, _____ becomes trapped as N5-methyl TH4, unable to participate in other carbon transfers.

Methyl Cobalamin Folate

Nucleotide metabolism allows the body to synthesize nucleotides as needed and to break down excess nucleotides into ___ ___. Nucleotide metabolism provides little ___.

Excretable products Energy

Nucleotides have many functions:

Nucleic acids, energy, second messenger cAMP, Allosteric regulators, ‘handles’ for cofactors such as NADH, CoSH, etc.

Key parts to a nucleotide: ____ is linked through a nitrogen to a ____ ___ which is linked to a ____.

Base Ribose sugar Phosphate

Nucleotide picture:

Purines: ___ and ___ Pyrimidines: ___ and ___

Adenine and Guanine Cytosine and thymine

Base and nucleoside pairs:

The ribose sugar component of nucleotides is derived from _____ _____ (PRPP).

5-phosphoribosyl 1-pyrophosphate

Purines are constructed by adding atoms from ______, glutamine, glycine, Aspartate, and carbon dioxide sequentially to ____ ____.

Formyltetrahydrofolate 5-phosphoribosyl 1-pyrophosphate

Pyrimidines are constructed by building the orotate base from ____, carbon dioxide, and ____. The bad is then transferred to ____ and further modified by cytosine, thymidine, and uracil.

Aspartate Glutamine 5-phosphoribosyl 1-pyrophosphate (PRPP)

PRPP is an activated ____ sugar created by transfer of _____ to ribose 5-phosphate by ___ ____, which is allosterically inhibited by ___ ____ (___ and ___). This is a key regulatory step in nucleotide synthesis.

Ribose Pyrophosphate PRPP synthetase Purine diphosphonucleosides (GDP and ADP)

Purine synthesis: The first committed step is the transfer of an ____ from glutamine by the ____ ____ ____. The second step is addition of glycine to make ____ ___ ____.

Amine Glutamine phosphoribosyl amidotransferase Glycinamide ribosyl 5-phosphate

Purine synthesis: ___ and ___ are added from N10-formyltetrahydrofolate, carbon dioxide, glutamine, and Aspartate to form _____ ____.

Carbon Nitrogen Inosine monophosphate (IMP)

Inosine monophosphate then gains an amine from _____ to form ____ ____, or an amine from ____ to form ___ ___.

Aspartate Adenosine monophosphate Glutamine Guanosine monophosphate

Purine synthesis: review of the urea cycle _____ is an amine donor in the urea cycle ____ is cleaved off arginosuccinate

Aspartate Fumarate

Purine synthesis: The conversion of ____ to ____ as an amine transfer simile to that in the urea cycle. ____ binds to IMP to make adenylosuccinate, then ____ is cleaved off to make ____. The energy to make adenylosuccinate comes from ____.

IMP AMP Aspartate Fumarate AMP GTP

Purine metabolism: Anaplerotic Through the purine nucleotide cycle, ___ from protein breakdown can supply ____ to the TCA cycle as an _____ substrate.

Aspartate Fumarate Anaplerotic substrate

Purine synthesis: To form guanosine monophosphate, ____ is first oxidized to ___ ____. Then an amine group is transfers from ____, using ATP hydrolysis to power the reaction.

IMP xanthine monophosphate Glutamine

Purine synthesis: Adenosine monophosphate and guanosine monophosphate are then ____ to diphosphates. ADP and GDP are then ____ again to make ___ and ___. OR the ribose sugar of ADP and GDP can be reduced to make ____ and ____.

Phosphorylated Phosphorylated ATP GTP dADP dGDP

Purine metabolism: ribonucleotide reductase: The #2 carbon on the ___ sugar of ADP and GDP (or UDP or CDP) can be ____ to dADP and dGDP. _____ is a protein redox cofactor that, like glutathione, can exist in reduce or oxidized states depending on ____ side chain sulfur atoms.

Ribose Reduced Thioredoxin Cysteine

Purine metabolism:

Ribonucleotide reductase (RR) uses ___ ____ as substrates.

Nucleoside diphosphates

Purine salvage: Because nucleoside synthesis requires a lot of energy, the body recycles them as much as possible. The goal of purine salvage pathway is to generate ____ and ____ from nucleotide degradation products.

AMP GMP

Purine salvage: To convert free bases to nucleotides, ______ (APRT and HGPRT) add ribose from _____ ____ (PRPP).

Phosphoribosyltransferases 5-phosphoribosyl 1-pyrophosphate

Purine salvage: To convert nucleosides to nucleotides, ____ ____ ____ removes ribose, leaving the free base.

Purine nucleoside phosphorylates

Purine salvage: Adenosine can be converted adenosine monophosphate (AMP) directly through phosphorylation by ___ ___.

Adenosine kinase

____ ____: cells expend a lot of energy to make nucleotides. To conserve this energy, there are different pathways to recycle nucleosides and bases in the cell.

Purine salvage

Purine salvage highlights:

Purine catabolism: GMP and AMP are degraded to _____, which is oxidized to uric acid by ____ ___, which uses a _____ atom in its catalytic site.

Xanthine Xanthine oxidase Molybdenum

Purine degradation can lead to ____ which is usually subclinical. However, ___ ___ is not very soluble, and purine degradation can lead to precipitation of ___ ___ in the distal joints causing ____.

Hyperuricemia Uric acid Uric acid Gout

Pyrimidines: In contrast to purines, which are assembled on a ribose sugar, Pyrimidine bases are first assembled then ____ to a ribose sugar.

Transferred

Pyrimidine synthesis: _____ ____ ____ ____ (CPS II) used glutamine as an amine donor to form carbamoyl phosphate. CPS II is allosterically inhibited by ____ and activated by ____.

Cytosolic carbamoyl phosphate UTP PRPP

Pyrimidine synthesis: Carbamoyl phosphate bonds with ____ to make carbamoyl Aspartate, which is then cyclized to ____.

Aspartate Orotate

Orotate combines with ____ to make a nucleotide, which is then decarboxylated to form ____ ____.

PRPP Uridine monophosphate (UMP)

Pyrimidine synthesis: recall from the urea cycle: ____ ____ is a substrate for Pyrimidine synthesis. Elevated urinary ___ ___ is characteristic of urea cycle disorders downstream of CPS-1.

Carbamoyl phosphate Orotic acid

Pyrimidine synthesis: ___ ___ only acts on the diphosphate form of nucleotides. ___ ___ uses dUMP as a substrate so dUDP has to be _____ before it can be methylated to dTMP. dTMP is then ____ twice to make dTTP, a substrate for ___ synthesis.

Ribonucleotide reductase (RR) Thymidine synthase Dephosphorylated Phosphorylated DNA

Blocking thymidine synthase deprives DNA polymerase of ____, preventing DNA replication. Cells that proliferate rapidly like cancer, immune cells, and gut epithelial cells are sensitive to ____ like ____ that target nucleotide synthesis.

dTTP anti-metabolites 5-fluorouracil

Pyrimidine catabolism: Unlike purine degradation, accumulation of Pyrimidine metabolites are not associated with ____.

Pathology

Pyrimidine catabolism: Cytosine is degraded to ____ Thymine is degraded to _____

Beta-alanine Beta-aminoisobutyrate

Disorders of nucleotide metabolism:

____ ____ ____ disorder results in overactivity of the enzyme by preventing inhibition by GDP. It is X-linked and only seen in males. Symptoms are due to increased ____ production and increases ___ ___. Mild form: Severe form:

PRPP synthetase superactivity Purine Uric acid Uric acid crystalluria, urinary stones, and gout arthritis Neurodevelopmental disorders

In PRPP synthetase superactivity disorder, the ___ ___ of the enzyme is lost.

Allosteric inhibition

Review:

Review case:

Case review:

Adenosine deaminase deficiency severe combined immunodeficiency:

Deficiency in adenosine deaminase is the second most common cause of autosomal recessive ____. Deficiency leads to accumulation of ___ and ____ in the blood. This is toxic to lymphocytes. Symptoms: Treatment:

SCID adenosine 2-deoxyadenosine Low lymphocyte count, costrochondal junction dysplasia Bone marrow transplant , chemotherapy

Review case:

____ ____ ____ deficiency is a rare cause if combined immunodeficiency. Symptoms include low but not absent T cells, chronic infections, failure to thrive, neurologic symptoms.

Purine nucleoside phosphorylase (PNP)

______ syndrome is a X linked syndrome caused by inherited deficiency in ____ ____ ____. Aka purine salvage disorder. Characterized by self injury. Elevated ___ ___ in urine, intellectual disability, dystonia, recurrent vomiting. Often die in 30’s from ___ failure. ____ can reduce uric acid and help prevent renal failure.

Lesh-Nyhan Hypoxanthine-guanine phopsphoribosyltransferase Uric acid Renal Allopurinol

Animal models suggest a disturbance in ___ ___ as a cause of self mitigation in Lesch-Nyhan.

Dopamine signaling

Purine catabolism disorder: gout: ____ is a structural analog of hypoxanthine. Xanthine oxidase oxides it to oxypurinal, which remains tightly to the active site, permanently inactivating ___ ___. ____ acts as a suicid inhibitor.

Allopurinol Xanthine oxidase Allopurinol

Nucleotide Metabolism Flashcards

(90 cards)