Puri ne metabol i sm

Salvage pathway of purine

Adenine + PRPP Adenylate + PPi

(AMP)

Mg 2+

APRTase

Catalyzed by adenine phosphoribosyl transferase (APRTase)

Hypoxanthine + PRPP Inosinate + PPi

( IMP)

Mg 2+

HGPRTase

Guanine + PRPP Guanylate + PPi

(GMP)

Mg 2+

HGPRTase

HGPRTase = Hypoxanthine-guanine phosphoribosyl transferase

Purine and pyrimidine degradation

Formation of uric acid from hypox anthine and xanthine catalysed by

xanthine dehydrogenase (XDH).

Adeni ne phosphori bosyl tran sferase defi ci ency

The normal function of adenine pho

sphoribosyltransferase (APRT) is th

e removal of adenine derived as me

tabolic waste from the polyamine p

athway and the alternative route of

adenine metabolism to the extreme

- ly insoluble 2,8 dihydroxyadenine,

which is operative when APRT is inactiv

e. The alternative pathway is catalysed

byxanthi ne oxi dase.

The salvage p athway of the

purine bases, hypoxanthine

and guanine, to IMP and G

MP, respectiv ely, catalysed

by HG PRT (1) in the presen -ce of PP ribos

- e P. The defec t in HPRT is sh

own.

The importance of HPRT in the norm

al interplay between synthesis and salva

ge is demonstrated by the biochemical a

nd clinical consequences associated with

HPRT deficiency.

Gross uric acid overproduction resul

ts from the inability to recycle either

hypoxanthine or guanine, which inte

rrupts the inosinate cycle producing

a lack of feedback control of synthes

is, accompanied by rapid catabolism

- - ofthesebases touri c aci d.PP ri bose Pnot ut

ilizedi nthe sal vage reacti onof the i nosi n

atecycl e i s consi deredtoprovi de anadd

itionalsti mul us tode novosynthesi s anduri

caci doverproducti on.

• HGPRT is determined by a gene -on the long arm of the x chromos

ome atXq2 6 .• Thedi sease i s transmi ttedas an

- X linked recessive trait.• - Lesch Nyhansyndrome•Al l opuri no lhas beeneff ecti v

ereduci ngconcentrati ons of u ricaci d.

Phosphoribosyl pyrophosphate synth

etase (PRPS, EC 2 .7 .6 .1 ) catalyse

s the transfer of the pyrophosphate group

- - -of ATPto ribose 5 phosphate to form PP

- riboseP.

The enzyme exists as a complex aggr

egate of up to 3 2 subunits, only the

1 6 and 3 2 subunits having signifi

cantactivity. It requires Mg2+ , is activat

ed by inorganic phosphate, and is su

bject to complex regulation by differentn

- ucleotide end products of the pathwa

- - ys for which PP ribose P is a substrat

e, particularly ADP and GDP.

Phosphoribosyl pyrophosphate synthetase superactivity

- - PP ribose P acts as an allosteric regulator of the first specific reacti

on of de novo purine biosynthesis, i n which the interaction of glutamin - - e and PP ribose P is catalysed by a

midophosphoribosyl transferase, p roducing a slow activation of the a

midotransferase by changing it fro m a large, inactive dimer to an activ

emonomer.

Purine nucleotides cause a rapid re versal of this process, producing th

ei nacti ve form.

Variant forms of PRPS have been de scribed, insensitive to normal regul

atory functions, or with a raised sp ecific activity. This results in contin - - uous PP ribose P synthesis which st

imulates de novo purine production , resulting in accelerated uric acid f

ormationandoverexcreti on.

- - The role of PP ribose P in the de novo s ynthesis of IMP and adenosine (AXP) a

nd guanosine (GXP) nucleotides, and t he feedback control normally exerted by these nucleotides on de novo purin

e synthesis.

•SCID because of dATP accumulation from dA phosphorylation – leading to RR inhibition (DNA synthesis choked off- cell proliferation blocked)

•Lymphoid tissue very active in dA phosphorylation

• The importance of adenosine deaminase (ADA) for the catabolism of dA, but not A, and the resu

ltant accumulation of dATP when ADA is defecti ve. A is normally salvaged by adenosine kinase and deficiency of ADA is not significant in this si

tuation

Adenine deaminase deficiency (SCID)

Purine nucleoside phosphorylase (PNP, EC 2 .4 .2 .1 )

• PNP catalyses the degradation of t he nucleosides inosine, guanosine

orthei r deoxyanal ogues to the corresp ondingbase.

• The mechanism appears to be the acc umul ati onof puri ne nucleotides whic

h are toxic to T cells.

• Less severe form of SCID as compared to ADA deficiency

• Useful in the treatment of autoimmune diseases such as rheumatoid arthritis, IDDM, T cell lymphomas and leukemias

Purine nucleos ide phosphoryla se deficiency

P urine nucleoside phosphorylase (PNP) is required for normal catabolism and salvage of b

oth nucleosides and deoxynucleosides. The lack of functional HG PRT activity, through absence o

f substrate, in PNP deficiency is also apparent.

P urine nucleotide cycle

AMPDA in the deamination of AMP to IMP, and the recon version of the latter to AMP via

Adenylosuccinate synthetase and lyase through adenylosuccinate

Fumarate is added on for enhanced Kreb’s cycle (anaplerotic reaction)

Patients suffer from fatigue and muscular cramps

Myoa denylate deaminase (A MPDA) deficiency

Intracellular uric acid crystal under polarised li - ght (left) and under non polarised light (right)

With time, elevated levels of uric acid in the blood may lead to deposits around joints. Ev

- entually, the uric acid may form needle like crystals in joints, leading to acute gout attac

ks. Uric acid may also collect under the skin or in the urinary tract as kidney stones.

Additional Gout Foot Sites: Inflamation In Joints Of Big Toe, Small Toe And Ankle

- Gout Early Stage: No Joint Damage

- Gout Late Stage: Arthritic Joint

Disorders of pyrimi dine metabolism

The UMP synthase (UMPS) complex, a bifunctional protei n comprising the enzymes orotic acid phosphoribosyltra

- - nsferase (OPRT) and orotidine 5' monophosphate decar boxylase (ODC), which catalyse the last two steps of the

de novo pyrimidine synthesis, resulting in the formation of UMP.

Symptoms: Secretion of orotic acid in urine, retarded growth and severe anemia

Treatment: administration of uridine and / or cytidine; UMP inhibits CPSII

Hereditary oro tic aciduria

Dihydropyrimidine dehydrogenase (DHPD) is responsib - le for the catabolism of the end products of pyrimidine

metabolism (uracil and thymine) to dihydrouracil and d ihydrothymine. A deficiency of DHPD leads to accumul

ation of uracil and thymine. Dihydropyrimidine amidoh ydrolase (DHPA) catalyses the next step in the further

catabolism of dihydrouracil and dihydrothymine to ami no acids. A deficiency of DHPA results in the accumulat ion of small amounts of uracil and thymine together wit

h larger amounts of the dihydroderivatives.

- CDP choline phosphotransferase ca talyses the last step in the synthesi

s of phosphatidyl choline. A deficie ncy of this enzyme is proposed as t

he metabolic basis for the selective accumulation of CDP- cholinei nthe erythro

cytesof rare pati ents wi thanunusual for mof haemol yti c anaemi a.

- CDP choline phosphotr ansferase deficiency