53. Purine metabolism

Question 1

Adenosine nucleoside function

Answer 1

binds to extracellular receptors, A1, A2a/b, A3 –> shows heart down and dilates capillaries.
Caffine is adenine derivative and antagonizes the effect of adenine –> heart can’t slow down.

Question 2

Nomenclature of purine

Answer 2

Base: adenine and guanine.
NucleoSIDE: adenosine, guanosine (base +sugar)
NucleoTIDE: base + sugar + phosphate.

Question 3

Activating nucleotides

Answer 3

Nucleoside monophosphate kinase (GMP + ATP –> GDP + ADP).

Nucleoside diphosphate kinase (XDP+YTP –> XTP+YDP)

Question 4

Common purine bases

Answer 4

Hypoxanthine (no amino group), xanthine (no amino group), adenine and guanine (both have amino groups).
Numbers on the rings go from upper left nitrogen on 6-membered ring to top of the ring in counter-clock-wise (1-6) then starts at 7 on the nitrogen on second ring clock-wise to 9.

Question 5

Purine de novo synthesis

Answer 5

1. PRPP synthesis
2. IMP synthesis
3. GMP synthesis
4. AMP synthesis

Question 6

Purine de novo synthesis: 1. PRPP synthesis

Answer 6

from pentose phosphate pathway: ribose 5P
R5P + ATP –> PRPP (by PRPP synthase).
Downregulated by IMP, AMP and GMP.

Question 7

Purine de novo synthesis: 2. IMP synthesis

Answer 7

PRPP + glutamine –> 5-phosphoribosylamine + glutamate + PPi. (by amidophosphoribosyl transferase).

5PPRamine –>–>–> IMP (inosine monophate=hypoxanthine +5RP).

Glycine: 2C+1N
5,10-methyl THF: 1C
10-formyl THF: 1C
2 glutamines: 2N
CO2: 1C+1O
Aspartate: 1N

Question 8

Purine de novo synthesis: 3. GMP synthesis

Answer 8

IMP + H2O + NAD –> XMP + NADP (by IMP DH).

XMP + gln + ATP –> GMP + glu + AMP + PPi (by GMP synthetase).

Question 9

Purine de novo synthesis: 4. AMP synthesis

Answer 9

IMP + aspartate + GTP –> adenylosuccinate + GDP (by adenylosuccinate synthetase)

Adenylosuccinate –> AMP + fumerate (by adenylosuccinase)

Question 10

Regulation of purine de novo synthesis

Answer 10

1. IMP, AMP, and GMP inhibit PRPP synthase and amidophosphoribosyl transferase (before and after PRPP).
2. AMP inhibits AMP synthesis; GMP inhibits GMP synthesis.
3. GTP stimulates AMP; ATP stimulates GMP

Question 11

Purine salvage pathways

Answer 11

PRPP + adenine –> AMP (by A-PRT)

PRPP + guanosine –> GMP (by HG-PRT)

Question 12

Purine degradation pathways

Answer 12

1. Guanine-specific
2. Adenine-specific
3. Common pathway

Question 13

Purine degradation pathway: 1. Guanine-specific

Answer 13

GMP –> guanosine (by nucleotidase)
Guanosine –> guanine (by nucleoside phosphorylase).
Guanine –> xanthine (guanine deaminase)

Question 14

Purine degradation pathway: 2. adenine-specific

Answer 14

AMP –> IMP (by adenylate deaminase)
Adenosine –> inosine (by adenosine deaminase; ADA).
IMP –> inosine (by nucleotidase; same as GMP–>guanosine)
Inosine –> hypoxanthine (by nucleoside phosphorylase; same as guanosine–>guanine).
Hypoxanthine –> xanthine (by xanthine oxidase)

Question 15

Purine degradation pathway: 3. Common pathway

Answer 15

Xanthine –> urate + H2O2 (by xanthine oxidase; same as the enzyme that converts hypoxanthine –> xanthine).

Question 16

3 metabolic diseases of purine metabolism

Answer 16

1. Gout
2. Lesch-Nyhan syndrome
3. SCID

Question 17

Gout

Answer 17

1. Decreased urate excretion (80%)
2. Increased urate production (20%).
   PRPP synthase overactivity (IMP, AMP and GMP cannot inhibit)
   HG-PRT defect: can’t make GMP from salvage pathway–> backed up PRPP increases de novo synthesis –> increases degradation –> increasead urate production.
   Exacerbated by alcohol, purine-rich diet and obesity.
   Tx: allopurinol competitively inhibits xanthine oxidase (last step in urate production); Colchicines decreases inflammation by inhibiting polymerization of microtubules.

Question 18

Lesch-Lyhan syndrome

Answer 18

Severe HG-PRT deficiency.
Decreased IMP & GMP –> increased PRPP and de novo synthesis of purines.
Sx: hyperuremia: gouty arthritis, k.stones, tophi; urate percipitation in CNS, self-injury (biting)

Question 19

SCID

Answer 19

Severe combined immunodeficiency syndrome.
AR disorder for mutation in ADA.
build-up of dATP is toxic to T and B cells.
susceptible to all sorts of infections.
Adenovirus expressing ADA was successfully employed as gene therapy in 1995.