Skildlum- Nucelotide Metabolism

Question 1

Which bases are purines?

Answer 1

GA

Question 2

Which bases are pyrimidines?

Answer 2

CT U

Question 3

What are hypoxanthine and inosine?

Answer 3

Intermediates when nucleotides are being converted to fuel sources

Question 4

What are nucleotide functions?

Answer 4

1. To make DNA and RNA
2. Handles“Handles” for enzyme cofactors:
   CoASH
   NAD+
   FAD
   Adenosylcobalamin
3. Energizing substrates–prepares them for reactions
   UDP-glucose
   CDP-choline
4. Second messengers
   cAMP
5. Allosteric activators
   AMP, ADP, ATP

Question 5

What is PRPP?

Answer 5

1. An activated ribose sugar

2. Created by the transfer of pyrophospahte to ribose 5 phosphate by PRPP synthetase

Question 6

What inhibits PRPP synthetase?

Answer 6

GDP and ADP

Question 7

What is the first step in purine synthesis?

Answer 7

The transfer of an amine from glutamine by the glutamine phosphoribosyl amidotransferase.

Question 8

What is the second step in purine synthesis?

Answer 8

Addition of glycine to make glycinamide ribosyl 5-Phosphate.

Question 9

How do you make IMP (inosine monophosphate)?

Answer 9

1. Add C and N from tetrahydrofolate
2. Add CO2
3. Add glutamine
4. Add aspartate

Question 10

What happens in the conversion of IMP to AMP?

Answer 10

1. Aspartate bonds to IMP to make adenylosuccinate (hydrolysis of GTP)
2. Fumarate is cleaved off to make AMP

Question 11

How do you form GMP?

Answer 11

1. IMP is oxidized to xanthine monophosphate

2. Amine group is transferred from glutamine (using ATP hydrolysis to power reaction)

Question 12

What happen to AMP and GMP?

Answer 12

1. Phosphorylated to diphosphates
   THEN
2. ADP and GDP can be phosphorylated again and: hydrolyzed for energy/incorporated into RNA
   OR
3. Ribose sugar of ADP and GDP can be reduced to make dADP and GDP

Question 13

What is thioredoxin?

Answer 13

A protein redox cofactor, like glutathione, that can exist in reduced or oxidized states depending on cysteine side chain sulfur atom.

Question 14

What happens in purine salvage?

Answer 14

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

Question 15

What can adenosine kinase do that is special? What must the other purine nucleosides do?

Answer 15

1. It directly phosphorylates Adenosine to AMP

2. Have their ribose sugars removed, then added back from PRPP, to make monophosphate nucleosides.

Question 16

What causes Lesch Nyhan Syndrome?

Answer 16

An inherited deficiency in hypoxanthine-guanine phophoribosyltransferase

Question 17

What causes SCID (Severe combined immunodeficiency)?

Answer 17

An inherited deficiency in adenosine deaminase

Question 18

What cause CID (Combined immunodeficiency)?

Answer 18

An inherited deficiency in purine nucleoside phosphorylase (PNP)

Question 19

What does PNP deficiency cause and what are the symptoms?

Answer 19

1. Combined immunodeficiency

2. Low but not absent T cells, chronic infection, FTT, neurological symptoms

Question 20

What is the second most common cause of autosomal recessive SCID?

Answer 20

ADA deficiency

Question 21

What does ADA deficiency lead to? What are the symptoms? What is the treatment?

Answer 21

1. Accumulation of 2 deoxyadenosine in the blood. This is toxic to lymphocytes.
2. Symptoms: Lymphocytes < 500 / mm3 (normal 3,000 – 9,000/mm3 for children), Costrochondral junction dysplasia (skeletal abnormalities)
3. Treatment: Bone marrow transplant, +/- chemotherapy

Question 22

What is Lesh Nhyan Disease? What are the symptoms?

Answer 22

HGPRT–He’s got purine recylcing trouble

1. A rare X linked syndrome due to inherited deficiency in hypoxanthine-guanine phosphoribosyltransferase.
2. Symptoms: Self injury (biting of the fingers and lips), Elevated uric acid in urine, mental retardation, dystonia, recurrent vomiting

Question 23

What do patients with LND often die from?

Answer 23

Renal failure in their 30s. Can be prevented with drugs (allipurinol) that reduce uric acid.

Question 24

What is the cause of self mutilation in LND?

Answer 24

Disturbance in dopamine signaling

Question 25

In purine metabolism, GMP and AMP are degraded to xanthine, which is oxidized to uric acid by what enzyme?

Answer 25

xanthine oxidase

Question 26

What is gout?

Answer 26

The precipitation of uric acid in distal joints, caused by purine degradation. **If you eat a lot of organ meat, you get a lot of nucleotides coming in that get degraded to uric acid. Xanthine oxidase makes uric acid, which is the normal rout of excretion for excess nucleotides. Treatment is a COMPETITOR of xanthine oxidase.

Question 27

How do purines and pyrimidines differ in synthesis/assembly?

Answer 27

1. Purines: assembled on ribose sugar | 2. Pyrimidines: assembled than transferred to ribose sugar

Question 28

What does CPS II do?

Answer 28

Uses glutamine as an amine donor to form carbamoyl phosphate. 2. Allosterically inhibited by: UTP, activated by PRPP

Question 29

How do you make UMP?

Answer 29

1. Carbamoyl phosphate bonds to aspartate to make carbamoyl aspartate. 2. This is cyclized to ORotATE 3. Orotate combines with PRPP to make a nucleotide, which is then decarboxylated to form UMP **Carbamoyl phosphate is used in urea cycle, but it is also a substrate for pyrimidine synthesis

Question 30

What is characteristic of urea cycle disorders downstream of CPS I?

Answer 30

Elevated urinary orotic acid

Question 31

What happens in pyrimidine degradation?

Answer 31

Cytosine > uracil > CO2, NH4+, and b-alanine Thymine > CO2, NH4+, and b-aminoisobutyrate **Accumulation of pyrmidine metabolites is not associated with pathology