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Medical Biochemistry > Nucleotide Anabolism > Flashcards

Nucleotide Anabolism Flashcards

1
Q

In addition to the salvage pathways, how else can purine and pyrimidines be synthesized? Where are the enzymes located in purine and pyrimidine synthesis?

A

de novo - from starting materials like CO2, NH3, and some of the AA Enzymes are in the cytosol

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2
Q

What are the sources of C and N atoms in pyrimidines?

A

Aspartate (donates 3C and 1N) Bicarb (donates 1C) Glutamine amide (donates 1N)

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3
Q

What are the steps in pyrimidine synthesis?

A

Amine from Glutamine Add CO2 Carbomyl Phosphate Add Aspartate Close the ring Orotic Acid Use PRPP to attach ribose-5-phosphate Remove CO2 to make Uridine (UMP) Cytosine or Thymidine From UMP, you can make Cytosine or Thymidine: UMP -> UDP -> UTP -> Cytosine UMP -> dUDP -> dUTP -> dUMP -> dTMP -> Thymidine

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4
Q

What vitamin do you need to make Thymidine, and why?

A

Folate, because it is the methyl source (N5, N10-methylene H4 folate is the source of CH3)

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5
Q

What does the drug 5-fluorouracil do to pyrimidine synthesis?

A

Prevents the cells from replicating. Used as a chemotherapy drug

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6
Q

How do pyrimidine and purine synthesis differ?

A

Pyrimidine: first we make the single ring, then add sugar, then add phosphate Purine: start with PRPP, add N, add and build up double rings from multiple sources

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7
Q

What are the sources of C and N atoms in purines?

A

Glutamine amide (2N) Glycine (1N, 2C) Aspartate amide (1N) Bicarb (1C) H4 Folate (2C)

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8
Q

What is the generic purine ring called?

A

IMP

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9
Q

How much ATP is required to synthesize a double ring purine?

A

4ATP (not including cost of PRPP)

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10
Q

What is the rate limiting step in pyrimdine synthesis?

A

CPS-2 is the rate-limiting step -glutamine + CO2 + 2ATP -> carbomyl phosphate + 2ADP + PPi

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11
Q

What happens if there is a defect in nucelotide anabolism?

A

Death (in utero)

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12
Q

What does GMP (Guanosine) require?

A

NAD, ATP, and NH2 from Gln

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13
Q

What does AMP (Adenosine) require?

A

GTP and NH2 from Asp

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14
Q

What comes from IMP?

A

GMP or AMP

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15
Q

What is the difference between Adenosine and Guanosine?

A

The placement of the amino group

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16
Q

How are the concentrations of AMP and GMP regulated?

A

The concentration of one affects synthesis of the other because you have to have A to make G and have to have G to make A. Keeps concentrations balanced

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17
Q

What does the antivrial drug Acyloguanosine (Acyclovir) do?

A

It impairs purine synthesis

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18
Q

How do mono-, di-, and triphosphate nucleotides relate?

A

They are all interconvertible: CMP + ATP CDP + ADP GDP + ATP GTP + ADP getting to triphosphate form traces back to oxidative phosphorylation because all ADP go back to ETS to get rephosphorylated

19
Q

What is the only version of Thymidine created?

A

It only exists in the oxidative form, ie. DEOXYribonucelotide

20
Q

HMPS generates NADPH. How is NADPH used?

A

In anabolic/synthetic pathways: fat synthesis as well as to make deoxy forms of nucleoides

21
Q

How is PRPP formed?

A

Ribose-5-P + ATP –> AMP + PRPP

22
Q

Where does the Ribose-5-P come from?

A

HMPS

23
Q

What enzyme catalyzes the synthesis of PRPP?

A

ATP phosphoribosyl transferase

24
Q

What inhibits ATP phosphoribosyl transferase?

A

The accumulation of purines and pyrimidines (product feedback inhibition)

25
Q

What happens if there is a deficiency in HGPRTase (as in Lesch Nyhan)?

A

Hypoxanthine and Guanine will accumulate because breakdown of nucleotides is occurring instead of recycling The accumulation blocks more PRPP synthesis, so all nucleotide synthesis is shutdown

26
Q

What is PRPP used for?

A

Purine and Pyrimidine de novo synthesis, NAD, and salvage pathways

27
Q

If ATP phosphoribosyl transferase is inhibited, what happens?

A

Accumulation of purines and pyrimidines –> Increase in purines causes an Increase in uric acid –> Gout

28
Q

What is the relationship between Glucose 6 Phosphatase deficiency (Type 1, von Gierke’s) and Gout?

A

G-6-phosphatase deficiency (Type I, von Gierke’s) –> increase G6P –> Glucose can’t be released from the liver cells –> Glucose gets pushed down HMPS pathway –> increase ribose-5-P –> increase PRPP –> increase nucleotide synthesis –> increase purines –> Gout (secondary)

29
Q

If you make more purines than you need, what happens?

A

Purines can’t be broken down for energy so you break them down. The waste products (uric acid) accumulate, and cause Gout

30
Q
A

Folate (vit B9)

31
Q

What is Folate’s involvement in Purine (Thymidine in particular) synthesis?

A

n5,10-methyleneH4folate is methyl donor in purine metabolism (in dUMP –> dTMP)

Folate is also required for Glycine <–> Serine and Homocysteine –> Methionine

32
Q

What clinical signs would you see in a folate deficicency?

A

Megaloblastic (pernicious) anemia

33
Q

What can interfere with folate absorption?

A

Antiseizure drugs

34
Q

Bacteria make their own folate. How can this be blocked?

A

Sulfonamide antibiotics target PABA

35
Q

What is needed to convert N5-methyl-H4 to H4-folate in mammals?

A

Cobalamin (Vit B12)

36
Q

What is B12 required for?

A

Folate absorption and Methionine synthesis

37
Q

What is needed to absorb B12?

A

Intrinsic Factor and Cobalt

38
Q

What drugs that inhibit dihydrofolate reductase (DHFR) and folate?

A

Certain Chemotherapy drugs, Antiprotozoal drugs, and Trimethorpim (an antibiotic used in combo with a Sulfonamide)

-they all mimic DHFR

39
Q

What clinical symptoms would appear in a patient with folate deficiency?

A

Low blood cell count (—Megaloblastic anemia, —Leukopenia, —Thrombocytopenia, —Pancytopenia)
—Atrophic glossitis
—Inappetance and weight loss
—Muscular weakness/fatigue
—Neurological/behavioral signs
Elevated levels of homocysteine in blood and urine (because can’t metabolize/breakdown/recycle homocysteine back to methionine)

40
Q

What diseases are correlated with folate deficiency?

A

Cardiovascular and Neural

41
Q

If Carbamyl phosphate could not be be synthesized into UMP, what clinical signs would arise?

A

Orotic acid would accumulate causing Orotic aciduria, decrease pyrimidine, not making DNA, low CTP and TTP, megaloblastic anemia from not making purines

42
Q

How do you treat Orotic aciduria?

A

Feed Uridine to produce pyrimidines which will push UMP –> UTP, which inhibits CPSII, decreasing orotate production

43
Q

A deficiency in Orotate phosphoribosyltransferase and/or orotidine-5’-P decarboxylase will cause what?

A

Orotic aciduria

Medical Biochemistry (13 decks)

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