Nucleotide Metabolism I

Question 1

What are nucleotides made up of?

Answer 1

Nitrogenous base - purine or pyrimidine

Ribose or 2-deoxyribose

Phosphate

Question 2

Why do we need to worry about nucelotides?

Answer 2

Components of nucleic acids

Energy metabolism

Components of coenzymes

Activated intermediates

Physiological modulators

Allosteric modulators

Question 3

What are the purine bases?

Answer 3

Adenine and Guanine

Intermediates are hypoxanithine and xanthine

Question 4

What are the pyrimidine bases?

Answer 4

Uracil

Cytosine

Thymine

Question 5

What is the nomenclature for a base + ribose?

Answer 5

Nucleoside

Question 6

What is the nomenclature for a base + ribose + phosphate?

Answer 6

Nucleotide

Question 7

Name the bases and their corresponding nucleosides

Answer 7

Adenine - Adenosine

Guanine - Guanosine

Cytosine - Cytidine

Thymine - Thymidine

Uracil - Uridine

Question 8

What are the characteristics of the de novo synthesis of purines?

Answer 8

Extremely energy intensive process

Salvage of pre-formed elements preferred

Purine ring assembled stepwise upon a base of 5-phosphoribosyl-1-pyrophosphate (PRPP) and generated by PRPP synthetase

Question 9

What is the importance of PRPP?

Answer 9

Participates in both purine and pyrimidine biosynthesis

Question 10

What is the committed step of de novo purine biosynthesis?

Answer 10

Formation of 5-phosphoribosylamine (PRA)

Catalyzed by amidophosphoribosyltransferase

Question 11

What is the first purine synthesized in the de novo synthesis of purines?

Answer 11

Inosine 5’-monophosphate (IMP)

Converted from 5-phosphoribosylamine (PRA)

Question 12

What are important characteristics of the formation of IMP from PRA?

Answer 12

Nine reactions convert PRA to IMP

Four reactions require ATP hydrolysis

Carbon and nitrogen atoms donated by amino acids

HCO3- contributes carbon and oxygen

N10-formyl THF donates one carbon groups

Question 13

What is IMP the precursor for?

Answer 13

AMP and GMP

Question 14

How is IMP converted to AMP?

Answer 14

AMP converted to adenylosuccinate by adenylosuccinate synthetase by adding aspartate

Adenylosuccinate converted to AMP by adenylosuccinase and fumarate is released

Question 15

What inhibits adenylosuccinate synthetase?

Answer 15

AMP

Question 16

How is IMP converted to GMP?

Answer 16

IMP converted to xanthosine 5’-monophosphate by IMP dehydrogenase and NADH and H released

Xanthosine 5’-monophosphate converted to GMP by GMP synthase and glutamate is released

Question 17

What inhibits IMP dehydrogenase?

Answer 17

GMP

Question 18

What is requires to convert AMP and GMP to ATP and GTP?

Answer 18

Kinase active

Nuceloside 5’-monophosphate kinases

Nucleoside 5’-disphosphate kinases

Question 19

What are the substrate specificities and examples of Nuceloside 5’-monophosphate kinases?

Answer 19

Differing substrate specificities

Adenylate kinase and guanylate kinase

Question 20

What are the substrate specificities and examples of Nucleoside 5’-disphosphate kinases?

Answer 20

Broad substrate specificity

Transfer phosphate from one nucleotide to another

Question 21

What does PRPP synthetase do and how is it regulated?

Answer 21

Converte ribose 5-phosphate to PRPP

Inhibited by purine nucleotides - ADP and GDP

Excess purine nucleotides reduces number of precursor molecule - self-limiting

PRPP required for purine and pyrimidine synthesis so both classes of nucleotides impacted

Question 22

What does amidophosphoribosyltransferase do and how is it regulated?

Answer 22

Converts PRPP to PRA

Committed step

Inhibited by AMP and GMP

Activated by PRPP - both substrate and allosteric activator

Increased PRPP stimulates purine synthesis

Question 23

What does adenylosuccinate synthetase do and how is it regulated?

Answer 23

Converts adenylosuccinate to AMP

Inhibited by AMP

Question 24

What does IMP dehydrogenase do and what regulates it?

Answer 24

Converts Xanthosine 5’-monophosphate to GMP

Inhibited by GMP

Question 25

Where does purine degradation occur largely?

Answer 25

Liver

Question 26

How does degradation of GMP occur?

Answer 26

Phosphate removed from GMP and generates guanosine by 5’-nucleotidase

Ribose removed from guanosine and generate free guanine by purine nucleoside phosphorylase

Question 27

How does degradation of AMP occur?

Answer 27

Utilizes two different aminases to convert AMP to inosine ->

AMP deaminase converts AMP to IMP and 5’ nucleotidase converts IMP and inosine

OR

5’nucleotidase converts AMP to Adenosine. Adenosine deaminase converts adenosine to inosine.

Inosine metabolized to hypoxanthine by purine nucleoside phosphorylase

Question 28

Where is AMP deaminase expressed and where is it abundant?

Answer 28

Widely expressed in skeletal muscle, brain, liver, and red blood cells

Abundant in muscle and loss of function can cause exercise intolerance. Sometimes called myoadenylate deaminase

Question 29

How is adenosine deaminase expressed and where is it abundant?

Answer 29

Widely expressed

Abundant in lymphocytes and loss of function impacts immune system

Question 30

How is uric acid generated?

Answer 30

Guanine and hypoxanthine converted to xanthine by guanine deaminase and xanthine oxidase, respectively.

Xanthine is then converted to uric acid

Question 31

What is the end product of purine degradation?

Answer 31

Uric Acid

Eliminated in urine

Question 32

What is uric acid and its characteristics?

Answer 32

Metabolic endpoint in humans and great apes

Weak acid

Question 33

What does it mean that uric acid and urate salts are both of limited solubility?

Answer 33

Urate levels in serum typically close to saturation even in normal, healthy individuals