Purine Biosynthesis and Regulation

Rondang R. Soegianto

2013
Purines and Pyrimidines =

Building blocks for foundation of

human life

(DNA, ATP, UDPglucose)

Purines and pyrimidines are
N-containing heterocyclic compounds
found as nucleoSides, nucleoTides and
polynucleotides (RNA, DNA)

Also as NAD, FAD, ATP, UTP, etc.

Purines& Pyrimidines are
N-bases or organic bases
Nonessential in food
Can be sufficiently synthesized in the body

Body does not synthesize free N-bases

but purine & pyrimidine nucleotides
de novo
Ingested nucleotides and nucleic acids
are degraded in intestinal tract

purine and pyrimidine bases.

Free absorbed bases from the intestinum

undergo degradation thru metabolic
processes.

Purines Uric acid

Harpers Review Fig 25-1 p348
Harpers ILL Table 32-1 p296
Nucleotides absorb UV light

Conjugated double bonds of purine and

pyrimidine absorb UV light
Mutagenic effect of UV light due to
chemical changes.
Synthetic nucleotide analogs

Used in chemotherapy
- Inhibit enzymes for nucleic acid synthesis
- Incorporation into nucleic acids
Disrupt base pairing

Also used for therapy are:

Synthetic purine and pyrimidine derivatves:
5-Fluorouracil, 5-Iodouracil, 6-
Mercaptopurine
Harpers Review Fig 26-2 p359
Biosynthesis of purine nucleotide
Ribosa-5P + ATP
Phosphoribosyl pyrophosphate (PRPP)
Enzyme: PRPPsynthase

First nucleotide synthesized = IMP

Other purine nucleotides synthesized from
IMP.
Harpers Review Fig 26-3 p360
Keep in mind:

- High energy consumption of purine

nucleotide biosynthesis de novo

- Importance of folate metabolism

One-C unit transporter
Effect on de novo synthesis
Harpers Review Fig 26-4 p361
 Purine Catabolism
Harpers Review Fig 26-1 p358
Metabolic Disorders of Catbolism

Purine catab.
Uric acid dissolves in blood as Na-urate,
which is normally excreted with urine.
Excessive Na-urate Hyperuricemia
Exceeding solubility limit
Na-urate crystallizes
Deposits in soft tissues and joints
Inflammation Gouty arthritis
Salvage Pathway

Purpose is energy conservation

De novo synthesis of purine (and pyrimidine)

nucleotides biosynthesis consumes high
energy

Key substrate is PRPP (also starting compound

for purine nucleotide biosynthesis)
Enzymes involved in salvage pathway

APRT: Adenine phosphoribosyl transferase

(acting on adenine)

HGPRT: Hypoxanthine-guanine phosphoribosyl

transferase
(acting on hypoxanthine or guanine)
Biochem & Disease Fig 16-3 p285
PPRP transfers 5-phosphoribosyl to free base

PPRP originates from:

- Pentosephosphate pathway (HMP shunt)

- Ribose-1-P Ribose-5-P
Enzyme: Phosphoglucomutase
Biochem & Disease Fig 16-4 p286
Energy cost in direct energy transfer

= 1 mole ATP per mole nucleotide

Thus saves 5 moles ATP per mole

nucleotide synthesis (profit of salvage pathway)
Other type of biosynthesis regulation:

Feedback control of nucleotide biosynthesis

regulation

Mechanism primarily controls

PPRP biosynthesis
Harpers Review Fig 26-11 p365
References:

Harpers Illustrated Biochemistry 27th ed. 2006

Harpers Review of Biochemistry 20th ed. 1985

Master Medicine. Medical Biochemistry 2nd ed. 2005

Biochemistry and Disease 1996