Disorders of Pyrimidine Metabolism

Dr. G. K. MaiyohDepartment of Medical

Biochemistry, School of Medicine, MU

April 13, 2023 1GKM/MUSOM/NSP 210:PATH.2012.2013

Lecturer:

Pyrimidines and Purines• Pyrimidine and purine are the names of the

parent compounds of two types of nitrogen-containing heterocyclic aromatic compounds.

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NN

NN

NN

NN

NNHH

PyrimidinePyrimidine PurinePurine

Important Pyrimidines• Pyrimidines that occur in DNA are cytosine

and thymine. Cytosine and uracil are the pyrimidines in RNA. HHNN

NNHH

OO

OO

UracilUracil

HHNN

NNHH

OO

OO

CHCH33

ThymineThymine

HHNN

NNHH

NNHH22

OO

CytosineCytosine

Synthesis Pathways• For both purines and pyrimidines there are two means

of synthesis (often regulate one another)– de novo (from bits and parts)– salvage (recycle from pre-existing nucleotides)

Salvage Pathwayde novo Pathway

Many Steps Require an Activated Ribose Sugar (PRPP)

5’

de novo Synthesis• Committed step: This is the point of no

return– Occurs early in the biosynthetic pathway– Often regulated by final product (feedback

inhibition)

X

Raw materials for biosynthesis

• Pyrimidine rings are synthesized independent of the ribose and transferred to the PRPP (ribose)

• Generated as UMP (uridine 5’-monophosphate)

• Synthesized from:– Glutamine

– CO2

– Aspartic acid

– Requires ATP

NC

CC

HN

C

O

CH3

HO

H

NC

CC

N

CH

O

H

H

NH2

Uracil Cytosine

How is Pyrimidine Biosynthesis regulated?

• Regulation occurs at first step in the pathway (committed step)

• 2ATP + CO2 + Glutamine = carbamoyl phosphate

Inhibited by UTPIf you have lots of UTP around this means you won’t make more that you don’t need. This is referred to as;

X

Biosynthesis: Purine vs Pyrimidine

• Synthesized on PRPP

• Regulated by GTP/ATP• Generates IMP• Requires Energy

• Synthesized then added to PRPP

• Regulated by UTP• Generates UMP/CMP• Requires Energy

Hereditary Orotic Aciduria• Is a defect in de novo synthesis of pyrimidines• Loss of functional UMP synthetase

– Gene located on chromosome III

• Characterized by excretion of orotic acid• Results in severe anemia and growth

retardation• Extremely rare (15 cases worldwide)• Treated by feeding UMP

Why does UMP Cure Orotic Aciduria?

CarbamoylPhosphate Orotate

UMPSynthetase

X

FeedbackInhibition• Disease (-UMP)

– No UMP/excess orotate

• Disease (+UMP)– Restore depleted UMP– Downregulate pathway via feedback inhibition (Less orotate)

Catabolism of pyrimidines

• Animal cells degrade pyrimidines to their component bases.

• Happen through dephosphorylation, deamination, and glycosidic bond cleavage.

• Uracil and thymine broken down by reduction (vs. oxidation in purine catabolism).

Pag

e 10

98

Pyrimidine Degradation/Salvage

• Pyrimindine rings can be fully degraded to soluble structures (Compare to purines that make uric acid)

• Can also be salvaged by reactions with PRPP– Catalyzed by Pyrimidine phosphoribosyltransferase

Degradation pathways are quite distinct for purines and pyrimidines, but salvage pathways are quite similar