purine synthesis | Quizlet

cAMP

cyclic adenosine monophosphate; involved in blood flow

cGMP

cyclic guanine monophosphate; second messenger

Secondary messengers in pyrimidines

Not common

Sources of nucleotides

Diet (exogenous); Synthesis (endogenous: direct synthesis and salvage)

RNA vs DNA synthesis

RNA is synthesized first; RNA is converted to DNA by removal of 2' OH

Nitrogen source in bases

Comes from amino acids

Purine synthesis goal

Create AMP and GMP

Purine synthesis ingredients

Ribose phosphate (HMP shunt); Amino acids; Carbons (tetrahydrofolate, CO2)

AMP & GMP components

Pentose (ribose sugar); 1 phosphate; Base (adenine or guanine)

Guanine base

Contains oxygen and nitrogen group

Adenine base

Contains nitrogen group

Step 1 purine synthesis

Create PRPP (phosphoribosyl pyrophosphate)

PRPP formation

Ribose-5-phosphate → PRPP

Source of ribose-5-phosphate

HMP shunt

Step 2 purine synthesis

Create IMP (inosine monophosphate)

IMP definition

Nucleotide with base hypoxanthine (intermediate)

PRPP to IMP

5-PRPP → IMP

Next enzyme after IMP

IMP dehydrogenase

Purine structure

2 rings with 4 nitrogens

6-membered ring

3 double bonds

5-membered ring

2 double bonds

Amino acids donating nitrogen (purines)

Aspartate: 1 N to 6-member ring; Glycine: 1 N to each ring; Glutamine: 1 N to each ring

Carbon sources (purines)

Glycine: 2 carbons; CO2: 1 carbon on 6-member ring; Tetrahydrofolate: 1 carbon to each ring

Tetrahydrofolate (THF)

Derived from folate; contributes to purine formation; single carbon donor

The deficiency of either B12 or folic acid inhibits?

purine nucleotides synthesis

Purine pathway summary

Ribose-5-phosphate → PRPP → IMP → AMP or GMP; requires aspartate, glutamine, glycine, THF, CO2

Rate-limiting enzyme purine synthesis

Glutamine-PRPP amidotransferase

Regulation of purine synthesis

↑ AMP/GMP → ↓ glutamine-PRPP amidotransferase

Deoxyribonucleotides

Lack 2' OH; used in DNA

Substrates for DNA polymerase:

dATP, dGTP, dTTP and dCTP

Deoxyribonucleotide synthesis

ADP/GDP → dADP/dGDP via ribonucleotide reductase

Ribavirin

Antiviral; inhibits IMP dehydrogenase; blocks IMP → GMP; inhibits guanine nucleotide synthesis

Mycophenolate

Immunosuppressant; inhibits IMP dehydrogenase in WBC; ↓ guanine → ↓ T & B cell replication

Purine salvage pathway

Recycles adenine, guanine, hypoxanthine → AMP, IMP, GMP; requires PRPP

HGPRT enzyme

Hypoxanthine guanine phosphoribosyltransferase

HGPRT function

Hypoxanthine → IMP; Guanine → GMP

APRT enzyme

Adenine phosphoribosyltransferase

APRT function

Adenine → AMP

6-mercaptopurine (6-MP)

Chemotherapy drug; mimics hypoxanthine/guanine; added to PRPP via HGPRT → thioinosinic acid → ↓ IMP, GMP, AMP

Azathioprine

Immunosuppressant; converted to 6-MP

Purine breakdown

Leads to uric acid excretion

Hypoxanthine breakdown

Hypoxanthine → xanthine → uric acid via xanthine oxidase

Guanine breakdown

Guanine → xanthine → uric acid (guanase + xanthine oxidase)

Adenine breakdown

Adenine → adenine-MP → adenosine → inosine (adenosine deaminase) → hypoxanthine → uric acid

Adenosine deaminase deficiency

Seen in SCID (severe combined immunodeficiency)

Uric acid excretion

Excreted by kidneys

Purine salvage malfunction (gout)

Excess uric acid; crystal deposition in joints → pain, swelling, redness (often big toe)

Causes of gout

Overproduction of uric acid (trauma, chemo); high purine diet (meat, seafood)

Gout treatment

Allopurinol inhibits xanthine oxidase

Azathioprine & 6-MP metabolism

Metabolized by xanthine oxidase → thiouric acid (inactive)

Allopurinol interaction

Inhibits xanthine oxidase → increases 6-MP levels (caution)

Lesch-Nyhan syndrome

X-linked HGPRT deficiency (purine salvage defect)

Lesch-Nyhan features

Excess uric acid (juvenile gout); ↑ de novo purine synthesis (↑ PRPP, ↑ IMP); hypotonia; chorea; self-mutilation behavior

Classic Lesch-Nyhan presentation

Boy with self-mutilation and gout

What catalyses the oxidation of uric acid to 5-hydroxyisourate?

urate oxidase, uricase, or factor-independent urate hydroxylase; absent in humans

Von Gierke

Glucose-6-phosphatase deficiency in the liver

Von Gierke mechanism

↑ Ribose-5-phosphate ↑ purine ↑ uric acids = Hyperuricemia