Inosine Monophosphate Imp Is Synthesized From Amphibolic Intermediates

Figure 34-2 illustrates the intermediates and reactions for conversion of a-D-ribose 5-phosphate to inosine monophosphate (IMP). Separate branches then lead to AMP and GMP (Figure 34-3). Subsequent phosphoryl transfer from ATP converts AMP and GMP to ADP and GDP. Conversion of GDP to GTP involves a second phosphoryl transfer from ATP, whereas conversion of ADP to ATP is achieved primarily by oxidative phosphorylation (see Chapter 12).

Multifunctional Catalysts Participate in Purine Nucleotide Biosynthesis

In prokaryotes, each reaction of Figure 34-2 is catalyzed by a different polypeptide. By contrast, in eu-karyotes, the enzymes are polypeptides with multiple catalytic activities whose adjacent catalytic sites facilitate channeling of intermediates between sites. Three distinct multifunctional enzymes catalyze reactions 3, 4, and 6, reactions 7 and 8, and reactions 10 and 11 of Figure 34-2.

Antifolate Drugs or Glutamine Analogs Block Purine Nucleotide Biosynthesis

The carbons added in reactions 4 and 5 of Figure 34-2 are contributed by derivatives of tetrahydrofolate. Purine deficiency states, which are rare in humans, generally reflect a deficiency of folic acid. Compounds that inhibit formation of tetrahydrofolates and therefore block purine synthesis have been used in cancer chemotherapy. Inhibitory compounds and the reactions they inhibit include azaserine (reaction 5, Figure 34-2), diazanorleucine (reaction 2), 6-mercaptopurine (reactions 13 and 14), and mycophenolic acid (reaction 14).

Respiratory CO2 Aspartate

Glycine /

N10-Formyl-tetrahydro-folate

Respiratory CO2 Aspartate

Glycine /

N10-Formyl-tetrahydro-folate

N5,N -Methenyl-tetrahydrofolate

Amide nitrogen of glutamine

Figure 34-1. Sources of the nitrogen and carbon atoms of the purine ring. Atoms 4, 5, and 7 (shaded) derive from glycine.

N5,N -Methenyl-tetrahydrofolate

Amide nitrogen of glutamine

Figure 34-1. Sources of the nitrogen and carbon atoms of the purine ring. Atoms 4, 5, and 7 (shaded) derive from glycine.

and therefore utilize exogenous purines to form nucleotides.

AMP & GMP Feedback-Regulate PRPP Glutamyl Amidotransferase

Since biosynthesis of IMP consumes glycine, glutamine, tetrahydrofolate derivatives, aspartate, and ATP, it is advantageous to regulate purine biosynthesis. The major determinant of the rate of de novo purine nucleotide biosynthesis is the concentration of PRPP, whose pool size depends on its rates of synthesis, utilization, and degradation. The rate of PRPP synthesis depends on the availability of ribose 5-phosphate and on the activity of PRPP synthase, an enzyme sensitive to feedback inhibition by AMP, ADP, GMP, and GDP.

"SALVAGE REACTIONS" CONVERT PURINES & THEIR NUCLEOSIDES TO MONONUCLEOTIDES

Conversion of purines, their ribonucleosides, and their deoxyribonucleosides to mononucleotides involves so-called "salvage reactions" that require far less energy than de novo synthesis. The more important mechanism involves phosphoribosylation by PRPP (structure II, Figure 34-2) of a free purine (Pu) to form a purine 5'-mononucleotide (Pu-RP).

Two phosphoribosyl transferases then convert adenine to AMP and hypoxanthine and guanine to IMP or GMP (Figure 34-4). A second salvage mechanism involves phosphoryl transfer from ATP to a purine ri-bonucleoside (PuR):

Adenosine kinase catalyzes phosphorylation of adeno-sine and deoxyadenosine to AMP and dAMP, and de-oxycytidine kinase phosphorylates deoxycytidine and 2'-deoxyguanosine to dCMP and dGMP.

Liver, the major site of purine nucleotide biosynthesis, provides purines and purine nucleosides for salvage and utilization by tissues incapable of their biosynthesis. For example, human brain has a low level of PRPP amidotransferase (reaction 2, Figure 34-2) and hence depends in part on exogenous purines. Erythrocytes and polymorphonuclear leukocytes cannot synthesize 5-phosphoribosylamine (structure III, Figure 34-2)

AMP & GMP Feedback-Regulate Their Formation From IMP

Two mechanisms regulate conversion of IMP to GMP and AMP. AMP and GMP feedback-inhibit adenylo-succinate synthase and IMP dehydrogenase (reactions 12 and 14, Figure 34-3), respectively. Furthermore, conversion of IMP to adenylosuccinate en route to AMP requires GTP, and conversion of xanthinylate (XMP) to GMP requires ATP. This cross-regulation between the pathways of IMP metabolism thus serves to decrease synthesis of one purine nucleotide when there is a deficiency of the other nucleotide. AMP and GMP also inhibit hypoxanthine-guanine phosphoribo-syltransferase, which converts hypoxanthine and gua-nine to IMP and GMP (Figure 34-4), and GMP feedback-inhibits PRPP glutamyl amidotransferase (reaction 2, Figure 34-2).

REDUCTION OF RIBONUCLEOSIDE DIPHOSPHATES FORMS DEOXYRIBONUCLEOSIDE DIPHOSPHATES

Reduction of the 2'-hydroxyl of purine and pyrimidine ribonucleotides, catalyzed by the ribonucleotide reductase complex (Figure 34-5), forms deoxyribonu-cleoside diphosphates (dNDPs). The enzyme complex is active only when cells are actively synthesizing DNA. Reduction requires thioredoxin, thioredoxin reductase, and NADPH. The immediate reductant, reduced thioredoxin, is produced by NADPH :thioredoxin re-ductase (Figure 34-5). Reduction of ribonucleoside diphosphates (NDPs) to deoxyribonucleoside diphos-phates (dNDPs) is subject to complex regulatory controls that achieve balanced production of deoxyribonu-cleotides for synthesis of DNA (Figure 34-6).

HN_pH

OH OH

HN_pH

OH OH

PRPP SYNTHASE

a-D-Ribose 5-phosphate

Glycine

H,Cs

"I

Glutamine Glutamate

PRPP GLUTAMYL AMIDOTRANSFERASE

NH Methenyl-

H4 folate H4 folate

j\| l/H ' ""a > H\| l/H I FORMYLTRANSFERASE I _ I-|H ATP ADP + P: H]-[H 1-1 O

OH OH

5-Phospho-ß-D-ribosylamine (III)

OH OH

Glycinamide ribosyl-5-phosphate (IV)

H2C5 7 8.H

Formylglycinamide ribosyl-5-phosphate (V)

-OOC

Fumarate

COO-

ADENYLOSUCCINASE

-OOC

-OOC

HC —NH3 Aspartate I

CH2 I

-OOC

IX SYNTHETASE

H2N'

Aminoimidazole succinyl carboxamide ribosyl-5-phosphate (IX)

Aminoimidazole carboxylate ribosyl-5-phosphate (VIII)

VI SYNTHETASE

'ATI

,Mg2

VII CARBOXYLASE

II CH

ATP, Mg 2+ H2O Ring closure

VII SYNTHETASE

Aminoimidazole ribosyl-5-phosphate (VII)

Aminoimidazole carboxamide ribosyl-5-phosphate (X)

N10-Formyl-H4 folate H4 folate

C

h2n"

1 FORMYLTRANSFERASE |

O=CN H

Ring closure

IMP CYCLOHYDROLASE

Formimidoimidazole carboxamide ribosyl-5-phosphate (XI)

Inosine monophosphate (IMP) (XII)

Formylglycinamidine ribosyl-5-phosphate (VI)

NH3+

Figure 34-2. Purine biosynthesis from ribose 5-phosphate and ATP. See text for explanations. (®, PO32 or PO2 .)

R-5-® Inosine monophosphate (IMP)

GTP, Mg2

ADENYLOSUCCINATE SYNTHASE

NAD+

R-5-® Inosine monophosphate (IMP)

NAD+

IMP DEHYDROGENASE

IMP DEHYDROGENASE

R-5-® Adenylosuccinate (AMPS)

ADENYLOSUCCINASE

R-5-® Adenosine monophosphate (AMP)

Figure 34-3. Conversion of IMP to AMP and GMP.

R-5-® Xanthosine monophosphate (XMP)

R-5-® Guanosine monophosphate (GMP)

Figure 34-3. Conversion of IMP to AMP and GMP.

Diabetes 2

Diabetes 2

Diabetes is a disease that affects the way your body uses food. Normally, your body converts sugars, starches and other foods into a form of sugar called glucose. Your body uses glucose for fuel. The cells receive the glucose through the bloodstream. They then use insulin a hormone made by the pancreas to absorb the glucose, convert it into energy, and either use it or store it for later use. Learn more...

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