13_Biochem Block 4.1 Nucleotide Metabolism

Front 1

Nucleoside vs Nucleotide? (P.353)

Back 1

Nucleoside is a glycosidic cmpd attached to a pentose sugar.
Nucleotide is an ester cmpd with a sugar and phosphate group attached.

Front 2

Re Purines and Pyrimidines, at what positions do they differ? (P.353)

Back 2

Purines differ only at positions 2 and 6.
Pyrimidines differ at positions 4 and 5.

Front 3

What is the precursor to all of the purines? Pyrimidines? (P.353)

Back 3

Purines = Hypoxanthine
Pyrimidines = Uracil

Front 4

In purines, where is the pentose typically attached? Pyrimidines? (P.354)

Back 4

Purines = C9
Pyrimidines = C1

Front 5

Where is the phosphate group typically added in the pentose sugar?

Back 5

C5

Front 6

Three sites of modification occur in pentose sugar. What are the locations and what happens there?

Back 6

C1 = glycosidic linage
C2 = oxy or deoxy occurs here
C5 = Phosphates

Front 7

Phosphates can be labelled alpha, beta, or gamma - which one is alpha?

Back 7

Alpha = closest to pentose ring.

Front 8

Cancer treatments often target this pathway: (P.355)

Back 8

Nucleotide metabolism

Front 9

What is the starting compound in purine de novo synthesis? What is the final compound before a branch point is reached? (P.355)

Back 9

PRPP = starting material
IMP = final cmpd before branching occurs

Front 10

What 4 aa's are used in purine nt synthesis and what doe they contribute? (P.355)

Back 10

Glutamine (1N), Glycine (1N, 2C), Glutamine (1N) and Aspartate (1N)

Front 11

how many ATP are required to make purine? (P.355)

Back 11

5 (4 for energy plus the original precursor molecule PRPP)

Front 12

How many carbon and nitrogens does glycine contribute? (P.355)

Back 12

2Cs and 1 N

Front 13

What does chemo drugs typically target in purine pathway? How many "formylations" does the purine synthesis rxn use and what doe they contribute?? (P.355)

Back 13

Tetrahydrofolate - uses two THF, each contributing 2 Cs

Front 14

How many CO2 molecules does the purine synth pathway use and how many Cs does it contribute?

Back 14

1 CO2 and 1 C

Front 15

When purine synthesis reaches IMP, the pathway branches - what do the two branches make?

Back 15

AMP and GMP

Front 16

What aa does the AMP branch use? How/where is IMP modified? What is its energy requirement? (P.356)

Back 16

AMP uses Aspartate; Oxygen at position 6 of IMP is replaced with amino group; Requires GTP

Front 17

What aa does the GMP branch use? How/where is IMP modified? What is its energy requirement? (P.356)

Back 17

GMP uses Glutamine; Amino group is added at IMP position 2. Energy requirement is ATP

Front 18

Where does the D-ribose-5-phosphate precursor to PRPP come from?

Back 18

Pentose phosphate pathway

Front 19

D-ribose-5-phosphate to PRPP via PRPP synthetase is NOT the committed step on de novo purine synthesis. Why? (p. 356)

Back 19

Bc PRPP can be used in other pathways and is not strictly used for purine nt synthesis.

Front 20

Overexpression of PRPP synthetase or increased enzymatic activity with altered kinetic properties has been documented in small subsets of what population?

Back 20

Gouty pts

Front 21

What enzyme is involved in the committed step on purine synthesis? What does it do? (p 357)

Back 21

ATase (Amidophosphoribosyltransferase). It desplaces pyrophosphate with the amino group of glutamine.

Front 22

How is ATase regulated (p 357)

Back 22

It is a dimer with its active site hidden. When PRPP is high enough, it induces monomerization and allows catalytic activity. When it purine nts get high enough, ATase is induced to dimerization/inactivation.

Front 23

What are the three multifunctional enzymes that are used in purine synthesis? Why does nature use these?

Back 23

GART, AIRC and Adenylosuccinate lyase. These enzymes are potentially used for three reasons:
1. Unstable intermediates
2. Efficiency
3. Toxic intermediates

Front 24

Synthesis and interconverstion of nucleoside diphosphates and triphosphates are mediated by different kinases. Which are base-specific and which are broadly specific? (p358)

Back 24

Monphosphate kinases are base-specific (Eg Adenylate Kinase and Guanylate Kinase). Diphophate kinases are broadly specific.

Front 25

Adenylate cyclase is important bc it regulates the ratio of ATP, ADP and AMP to what? (p358)

Back 25

100:10:1, respectively

Front 26

Review figure on p 359 for says that purine synth is regulated

Back 26

Review figure on p 359 for says that purine synth is regulated

Front 27

What are the three key rxn in catabolysis of purine nts?

Back 27

1. Dephosphorylation
2. Deamination
3. Phosphorolysis

Front 28

In the first step of AMP degradation, two paths can be taken - this results in ?? or ?? Why is this important? (p359)

Back 28

IMP or Adenosine. IMP is produced in exercising skeletal muscle and facilitates the net resynthesis of ATP following exercise. Adenosine is produced in ischemic or anoxic heart - it is a potent coronary vasodilator that facilitates oxygen delivery back to damaged tissue.

Front 29

Memorize basic degradation pathway on pg 359?

Back 29

Memorize basic degradation pathway on pg 359?

Front 30

How does ischemia cause increase production of free radicals?

Back 30

XDH and XO are used to convert hypoxanthine to uric acid. Under ischemic conditions, XDH is converted to XO and XO uses O2 to produce Xanthine and hydrogen peroxide as a byproduct. The H2O2 is toxic

Front 31

What are the three ways someone can have Primary Gout? (p361)

Back 31

1. Overexpression of PRPP
2. Deficiency of HPRT salvage pathway enzyme
3. Urate excretion deficiency

Front 32

What two things can cause Secondary Gout?

Back 32

1. Drug intake
2. Unusual dietary habit

Front 33

What is allopurinol and what is the mechanism by which it works? (p361)

Back 33

It is an analogue of hypoxanthine that inhibits XDH (xanthine dehydrogenase). This shunts excess hypoxanthine through the salvage pathway, increases nts that inhibit ATase and therefore urate.

Front 34

Second to Urate, what is the most insoluble purine base in the body? What deficiency causes this? How is accumulation of this compounded treated?

Back 34

Xanthine. Excess caused by a deficiency in Xanthine Dehydrogenase. Only way to reduce this is via diet.

Front 35

What two deficiencies cause SCID?

Back 35

Adenosine Deaminase (ADA) and Purine nucleoside phosphorylase (PNP).

Front 36

What is the mechanism by which ADA and PNP cause SCID?

Back 36

dATP or dGTP accumulates in lymphocytes. This excess inhibits ribonucleotide reductase responsible for producing all of the dNTPs necessary for DNA synthesis.

Front 37

What are the two ways that purine nucleotides can be produced in the salvage pathway? How much energy is required? (p363)

Back 37

1. a) Adenine phosphoribosyltransferase (APRT) attaches PRPP directly to adenine to produce AMP
b) Hypoxanthine-guanine phosphoribosyltransferase (HPRT) can add PRPP directly to Hypoxanthine or Guanine to produce IMP or GMP, respectively.
2. ATP can be directly attached to a purine nucleoside.
**Both require 1 ATP vs 5

Front 38

In Lesch-Nyhan syndrome, what pathway is defective and what enzyme is deficient? (p364)

Back 38

Salvage pathway is defective and caused by deficiency in HPRT

Front 39

What is the inheritance of Lesch-Nyhand syndrome? (p364)

Back 39

X-linked

Front 40

With a deficiency in HRPT, what symptoms would you expect? (p364)

Back 40

You would expect a decrease in salvage pathway shunting and an increase in Urate and therefore gout. There would also be an increased rate of PRPP synthesis and de novo purine synthesis.

Front 41

A nice review of lecture 1

Back 41

A nice review of lecture 1