Nuelcotide Metabolism Lecture Sep 10

Question 1

What are the associated nucleosides to these bases:

Adenine

Guanine

Hypoxanthine

Cytosine

Thymine

Uracil

Answer 1

Adenosine

GUanosine

Inosine

Cytidine

Thymidine

Uridine

Question 2

What are 5 functions of nucleotides?

Answer 2

1. Formation of genetic information (DNA, RNA)
2. Handles for enzyme cofactors (CoASH, NAD, FAD, Adenosylcobalamin)
3. Energizing substrates (UDP-glucose, CDP-choline)
4. Second messengers (cAMP)
5. Allosteric activators (AMP, ADP, ATP)

Question 3

What molecule is the main basis for nucleotide syntehsis?

How is it synthesized?

Answer 3

5-phosphoribosyl 1-pyrophosphate (PRPP)

This is an activated ribose sugar created by transfer of pyrophosphate to ribose 5-phosphate by PRPP synthetase.

Question 4

What enzyme synthesizes PRPP?

How is it regulated?

Answer 4

PRPP Synthetase

Allosterically inhibited by purine diphosphonucleosides like GDP and ADP

(this is feedback inhibition)

Question 5

In purine synthesis, what important intermediate is PRPP used to synthesize?

What is added onto this intermediate to form AMP?

WHat is added onto this intermediate to form GMP?

Answer 5

PRPP is used to synthesize Inosine Monosphosphate

Aspartate binds to IMP (and then fumarate is cleaved off() to make AMP

To make GMP, IMP is first oxidize to form XMP, to which glutamate donates an amine group to form GMP.

Question 6

Through the purine synthesis pathway, what is synthesized first?

ribonucleic acid or deoxyribonucleic acid?

Answer 6

ribonucleic acid (for RNA)

Question 7

WHat additional enzyme is required to convert ribonucleotides to deoxyribonucleotides?

What are its cofactors?

Answer 7

Ribonucleotide Reductase!

It uses thoredoxin as a cofactor, which is regenerated through oxidation of NADPH (provided by the pentose phosphate pathway)

Question 8

What purine nucleoside can be directly phosphorylated to its nucleotide without any intermediates?

How must the other purine nucleosides go about it?

Answer 8

Adenosine can be directly phosphorylated to AMP by adenosine kinase.

The other purine nuclosides must have their ribose sugars removed, then added back from PRPP to make their monophosphate nucleotides

Question 9

What disorder results from a deficiency in hypoxanthin/guanine phosphorivosyltransferase (PRP)?

Answer 9

Lesch-Nyhan SYndrome

Question 10

What disorders results from a deficiency in adenosine deaminase?

Answer 10

Severe combined immunodeficiency (SCID)

Question 11

What disorder results from a deficiency in purine nucleoside phosphorylase (PNP)

Answer 11

Combined immunodeficiency (CID)

Question 12

Describe CID.

Symtpoms?

Answer 12

THis is a defect in purine nucleoside phosphorylase (PNP), so nucleosides can’t be recycled to make free bases.

Inosine and Guanosine build up.

THe hallmark of this disorder is that they have normal B cells, but low (now abscent) T-cells

THey often have chronic infection, FTT, and neurological symptoms

Question 13

Describe SCID.

Symptoms?

Treatment?

Answer 13

This is a deficiency in adenosine deaminase (ADA)

this leads to an accumulation of 2-deoxyadenosine in the blood, which is toxic to lymphocytes.

Hallmark is an extremely low WBC with a total lack ot T and B cells

You also get costrochondral junction dysplasia

Treatment is a bone marrow transplate with or without chemotherapy

Question 14

Describe Lesch Nyhan Disease.

Answer 14

It’s a rar x-linked (boys only!) due to inherited deficiency in HGPRT.

This is characterized by self injury (often bitin fingers and lips)

Elevated uric acid in urine (leading to gout), MR, dystonia, recurrent vomiting

Often die in 30s due to renal failure

Question 15

What is a likely cause of the self mutilation behavior in LND?

Answer 15

Disturbance in dopamine signalling

Question 16

How is purine metabolism related to gout?

Answer 16

GMP and AMP are degraded to xanthine, which is oxidized to uric acid by xanthine oxidase.

If degradation is occuring rapidly, this can lead to hyperuricemia.

Uric acid is not very soluble, so if it builds up, it can precipitate out as uric acid in the distal joints, causing gout.

Question 17

WHat is the treatment for gout?

How does it work?

Answer 17

Allopurinol

It acts as a competitive inhibitor of xanthine oxidase, so you don’t get uric acid buildup, and no precipitation.

Xanthine and hypoxanthine build up, but these are less likely to precipitate out and cause harm.

Question 18

What other cycle does pyrimidine synthesis intersect with? Through what molecule?

Answer 18

Pyrimidine synthesis intersects with the urea cycle through carbamoyl phosphate.

Question 19

In general, how does pyrimidine synthesis differ from purine synthesis?

Answer 19

While purine synthesis involves building onto the PRPP molecule by molecule, pyrimidine synthesis involves building the whole base and then transferring it en bloc onto PRPP.

Question 20

What does cytosolic carbamoyl phosphate synthase do? How does this differ from mitochondrial cytosolic carbamoyl phosphate synthase?

How is it regulated?

Answer 20

CPS II uses glutamine as an amine donor to form carbamoyl phosphate.

THis differs from CPS I, which used free amine for form carbamoyl phosphate.

CPS II is allosterically inhibited by UTP (feedback inhibition) and activated by PRPP (feedback activation).

Question 21

What molecule gets added to the PRPP in pyrimidine syntheiss?

Answer 21

orotate (orotic acid)

Question 22

WHat does cytosine degrade to?

What does thymind degrade to?

Answer 22

Cytosine ——> betal-alanine

Thymine ——-> beta-aminoisobutyrate

plus Co2 and NH4

Accumulation of pyrimidine metabolites is not associated with pathology