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Medical Biochemistry > Topic 17: Nucleotide Anabolism > Flashcards

Topic 17: Nucleotide Anabolism Flashcards

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1
Q

Can all the nucleotides be built from scratch in the body?

A

YES, they can all be synthesized de novo.

There are no essential nucleotides required in the diet.

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2
Q

What are pyrimidines anabolized from?

A

HCO3, Glutamine, Aspartate

Mostly Aspartate (4 of 6 atoms worth)

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3
Q

What is step 1 of Pyrimidine synthesis?

A

Glutamine (Gln) –> use 2 ATP and add CO2 via CPS-2 –> Carbamoyl Phosphate + Glu

CPS-2 = Carbamoyl-Phosphate Synthetase-2 in cytosol

THIS IS THE RATE LIMITING STEP

(Note: CPS-1 was in the UREA cycle in mitochondria)

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4
Q

What is Step 2 of Pyrimidine synthesis?

A

add Aspartate to Carbamoyl Phosphate to make Carbamoyl Aspartic Acid

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5
Q

What is Step 3 of Pyrimidine synthesis?

A

Close the ring and add H to make Orotic Acid

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6
Q

What is Dr. Eng’s favorite molecule of pyrimidine synthesis? (lol)

A

OROTIC ACID

sounds like erotic acid

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7
Q

What is Step 4 of Pyrimidine synthesis?

A

Use PRPP to attach Ribose-5-Phosphate

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8
Q

What is Step 5 of Pyrimidine synthesis?

A

Remove CO2 via decarboxylase to make Uridine Monophosphate (UMP)

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9
Q

What is Step 6 of Pyrimidine synthesis?

A

UMP => UDP

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10
Q

What is Step 7a and 7b of Pyrimidine synthesis?

A

7a) UDP -> UTP add another amino group -> CTP
7b) UDP converted to deoxyUDP (DNA synthesis) -> dUDP plus methyl group -> dUTP -> dUMP plus methyl from N5,10-MethyleneTetrahydrofolate -> dTMP

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11
Q

What is one way pyrimidine synthesis is regulated?

A

UTP inhibits CPS-2, the first and rate-limiting step of pyrimidine synthesis

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12
Q

What explicitly did Dr. Eng want us to know about pyrimidine synthesis pathway?

A

Glutamine + CO2–> starting off to make Carbamoyl Phosphate then you add Aspartate

eventually to Orotic Acid which goes to UMP, which can be made into other precursors

to make Thymidine you MUST have N5,10-methylenetetrahydrafolate (From Glycine->Serine; must also have FOLATE/FOLIC ACID/Vitamin B9)

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13
Q

What structures might you want to know for the exam?

A

Orotic Acid; Folic Acid/B9 or anything with folate in it; Purine vs. Pyrimidine (double vs. single ring);

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14
Q

Describe Purine synthesis at a glance.

A

All enzymes in cytosol

1) Starts with PRPP/sugar-phosphate (pyrimidines started with ring then adds sugar-phosphate)
2) Replace C1 with N from Glutamine
3) Add Glycine and carbons from H4folates and HCO3 and more N’s from Glutamine and Aspartate
4) End up with IMP

Used 4 ATP not including cost for PRPP (ATP=>AMP so 2 equivalents) = 6 equivalents overall

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15
Q

What is Step 1 in deriving GMP from IMP?

A

IMP via IMP Dehydrogenase –> Xanthosine-5-monophosphate (XMP)

NAD+-> NADH is generated

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16
Q

What is Step 2 in deriving GMP from IMP?

A

XMP via GMP-synthetase takes an amino from Gln –> GMP

ATP –> AMP + PPi to power the reaction

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17
Q

What is Step 1 in deriving AMP from IMP?

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A

IMP via adenylsuccinate synthetase adds Aspartate –> Adenylosuccinate

GTP –> GDP + Pi to power the reaction

18
Q

What is Step 2 in deriving AMP from IMP?

Study These Flashcards
A

Adenylosuccinate via adenylosuccinase removes Fumarate –> AMP

19
Q

What is the difference between purine anabolism from IMP?

Study These Flashcards
A

GMP: requires NAD+, ATP and NH2 from Gln

AMP: requires GTP, and NH2 from Asp

20
Q

How do GMP and AMP affect the synthesis of one another?

Study These Flashcards
A

To make G, this is powered by ADP!
To make A, this is powered by GDP!

In this way, the concentration of one affects the synthesis of the other

21
Q

What is Acyclovir?

Study These Flashcards
A

Antiviral Drug that interrupts DNA synthetic machinery. Especially used for Herpes.

22
Q

How are DEOXYribonucleotides formed?

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A

Ribonucleotide Reductase converts ribonucleotide to deoxyribonucleotide using NADPH –> NADP+

23
Q

How is PRPP synthesized?

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A

Ribose-5-phosphate from HMPS and ATP via ATP Phosphoribosyl transferase ==> PRPP + AMP

This is a major control step for nucleotide synthesis since PRPP is absolutely essential for both purines and pyrimidines.

ATP-Phosphoribosyl transferase is INHIBITED by high concentrations of purines and pyrimidines.

24
Q

Link Lesch-Nayan Syndrome (HGPRTase deficiency) with PRPP inhibition.

Study These Flashcards
A

HGPRTase (salvage enzyme) deficiency tends to cause accumulation of Hypoxanthine and Guanine (normally we recycle at least half of them)–> buildup causes inhibition of PRPP synthesis –> all nucleotide synthesis is fucked.

Even though the other nucleotides are fine, the buildup of one will turn off PRPP synthesis.

25
Why does inhibiting PRPP synthesis tend to cause gout?
Inhibiting PRPP synthesis pushes towards Uric Acid formation since there is no ability for salvage pathway (which requires PRPP) --> Uric Acid buildup --> Gout!
26
How come animals with Von Gierke's (Glycogen Storage Disease 1) tend to have gout?
Glucose-6-Phosphatase deficiency --> cannot release glucose to blood --> high amounts of Glucose-6-Phosphate in cell pushes to HMPS --> high amounts of PRPP are then made --> increase nucleotide synthesis like crazy --> purines go up, SO URIC ACID formation goes up --> Secondary Gout! This is one of Dr. Eng's favorite correlations. I would suggest you know this.
27
What happens to folate once we ingest it?
Folate via Folate Reducatse --> H2-folate NADPH -> NADP+ H2-folate via H2-folate reductase --> H4-folate NADPH -> NADP+ H4-folate is important for several pathways, notably Thymidine formation.
28
What is the 1 carbon pool?
Folate eventually becomes a single carbon donor for glycine/serine metabolism and thymine and purine synthesis. Review Slide 13 Topic 17: Nucleotide Anabolism
29
Why is folate important?
Absolutely necessary for thymidine and Purine synthetic pathways.
30
How can bacterial folate (p-aminobenzoic acid/PABA) synthesis be inhibited?
Sulfonamide antibiotics --> therefore preventing DNA synthesis
31
What is one of the first things that shows up in Vitamin B9/Folic Acid deficiency?
Megaloblastic (Pernicious) Anemia -- Really big RBCs but not enough RBCs.
32
What drugs could interfere with folate absorption from the gut?
Phenytoin, Primidone, Phenobarbital (anti-seizure drugs)
33
What vitamin is needed for B9/Folate absorption?
Vitamin B12/Cobalamin
34
Where do we get Vitamin B12/Cobalamin?
from the diet - we need Intrinsic Factor which is produced in the stomach.
35
What cofactor does Vitamin B12/Cobalamin require?
Cobalt! It is a normal constituent of Vitamin B12
36
When would B9/B12 absorption be an issue?
Older animals, shrunken stomachs - not enough intrinsic factor --> deficient B12 --> deficient B9 Recent stomach surgery - impaired stomach function leads to impaired intrinsic factor synthesis/release --> deficient B12 --> deficient B9
37
What is Dihydrofolate reductase?
The enzyme that converts dihydrofolate (H2-folate) to tetrahydrofolate (H4-folate) in the recycling/synthetic process of the 1 carbon pool, H4-folate.
38
What are drugs that inihbit H2-folate Reductase?
Methotrexate, Aminopterin (chemotherapy) Pyrimethamine (antiprotozoal) with sulfadiazine (sulfonamide) Trimethoprim (antibiotic) with sulfamethoxazole (sulfonamide) --> great for treating tissues hard to reach/low blood supply (bladder, lungs, urinary tract)
39
What do folate deficiencies look like?
Megaloblastic Anemia Leukopenia Thrombocytopenia Pancytopenia (deficient in everything) Atrophic glossitis (tongue inflammation) Inappetance/weight loss Muscular failure and fatigue Neurological and behavioral signs
40
How does folate deficiency affect homocysteine and methionine metabolism?
Results in elevated levels of homocysteine in blood and urine --> correlated with cardiovascular and neural diseases in people
41
What is orotic aciduria?
Hereditary deficiencies in enzymes downstream will result in low Pyrimidines (CTP and TTP) --> not making DNA --> Megaloblastic Anemia and Growth Retardation Treat by feeding URIDINE to feedback inhibit (CPS-2 is inhibitied) the production of Orotic Acid.
42
What is NADPH needed for?
``` Anabolism of: Glutamate from a-KG H4-folate (twice from folate) nucleotide anabolism (twice) Fatty Acid synthesis ```

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