Inosine 5 -monophosphate synthesis

Inosine, 6-benzyloxy-9- -D-ribofuranosyl-2-dimethylamino-hydrogenolysis, 5, 558 Inosine, 2 -deoxy-alkylation, 5, 538 Inosine, 6-phenacylthio-dethiation, S, 559 Inosine 5 -monophosphate biosynthesis, 1, 88 Inosines, thio-synthesis, 5, 584 Inositol, D-l,4-anhydro-synthesis, 1, 416 Inositols synthesis, 1, 416 Insecticides... 

Inosine monophosphate dehydrogenase (EVDPDH) is a key enzyme of purine nucleotide biosynthesis. Purine synthesis in lymphocytes exclusively depends on the de novo synthesis, whereas other cells can generate purines via the so-called salvage pathway. Therefore, IMPDH inhibitors preferentially suppress DNA synthesis in activated lymphocytes. 

Inosine monophosphate dehydrogenase (IMPDH) is the key enzyme of purine nucleotide biosynthesis. Proliferation of activated lymphocytes dq ends on rapid de novo production of purine nucleotides for DNA synthesis. 

Mycophenolate mofetil was approved by the FDA in 1995, and enteric-coated mycophenolic acid was approved in 2004. Both agents are considered to be adjunctive immunosuppressants. Mycophenolic acid acts by inhibiting inosine monophosphate deydrogenase, a vital enzyme in the de novo pathway of purine synthesis. Inhibition of this enzyme prevents the proliferation of most cells that are dependent on the de novo pathway for purine synthesis, including T cells.7,11,26-28... 

Figure 20.8 Summary of pathways for de novo synthesis of purine and pyrimidine nucleotides. C represents transfer of a single carbon atom (a one-carbon transfer). Details are provided in Appendix 20.1. IMP - inosine monophosphate. For thymi-dylate synthesis, see Figure 20.12a.

In the purine nucleotide pathway, the purine nucleotide is synthesised upon the phosphoribose using several small molecules. The first purine nucleotide formed is inosine monophosphate (IMP) it is an intermediate on the pathway for the synthesis of both adenine and guanine nucleotides (Figure 20.8). 

Mycophenolate sodium (62 Myfortic Norvatis, 2003) is an immunosuppressant drug used to prevent rejection in organ transplantation. It is a selective, noncompetitive, reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH), the rate-limiting enzyme in the de novo pathway of guanosine nucleotide synthesis. Thus, mycophenolic acid (61), originally... 

Mycophenolate mofetil has a more specific effect on lymphocytes than on other cells. It inhibits inosine monophosphate dehydrogenase, which catalyzes purine synthesis in lymphocytes. It is used in acute tissue rejection responses. 

The major intermediates in the biosynthesis of nucleic acid components are the mononucleotides uridine monophosphate (UMP) in the pyrimidine series and inosine monophosphate (IMP, base hypoxanthine) in the purines. The synthetic pathways for pyrimidines and purines are fundamentally different. For the pyrimidines, the pyrimidine ring is first constructed and then linked to ribose 5 -phosphate to form a nucleotide. By contrast, synthesis of the purines starts directly from ribose 5 -phosphate. The ring is then built up step by step on this carrier molecule. 

Figure 10-2. Regulation of purine synthesis by the nucleotides and the intermediate, 5 -phosphoribosyl-1 -pyrophosphate (PRPP). Both feedback and feed-forward mechanisms are utilized in this intricate scheme. IMP, inosine monophosphate.

Mycophenolate mofetil is used together with cyclosporine and corticosteroids for the prophylaxis of acute organ rejection in patients undergoing allogeneic renal, or hepatic transplants. Compared with azathioprine it is more lymphocyte-specific and is associated with less bone marrow suppression, fewer opportunistic infections and lower incidence of acute rejection. More recently, the salt mycophenolate sodium has also been introduced. Mycophenolate mofetil is rapidly hydrolyzed to mycopheno-lic acid, its active metabolite. Mycophenolic acid is a reversible noncompetitive inhibitor of inosine monophosphate dehydrogenase, an important enzyme for the de novo synthesis of purines. As lymphocytes have little or no salvage pathway for purine... 

Mycophenolate mofetil (MMF, CellCept) is an ester prodrug of mycophenolic acid (MPA), a Penicillium-de-rived immunosuppressive agent (see Chapter 57) that blocks de novo purine synthesis by noncompetitively inhibiting the enzyme inosine monophosphate dehydrogenase. MPA preferentially suppresses the proliferation of cells, such as T and B lymphocytes, that lack the purine salvage pathway and must synthesize de novo... 

Mechanism of Action An immunologic agent that suppresses the immunologically mediated inflammatory response by inhibiting inosine monophosphate dehydrogenase, an enzyme that deprives lymphocytes of nucleotides necessary for DNA and RNA synthesis, thus inhibiting the proliferation of T and B lymphocytes. Therapeutic Effect Prevents transplant rejection. 

Unlike these nonspecific agents, mycophenolate mofetil (6.4) tends to be a lymphocyte-specific cytotoxic agent. Mycophenolate mofetil is a semisynthetic derivative of mycophe-nolic acid, isolated from the mold Penicillium glaucum. It inhibits both T and B lymphocyte action. Since it inhibits the enzyme inosine monophosphate dehydrogenase, which catalyses purine synthesis in lymphocytes, this agent has a more specific effect on lymphocytes than on other cell types. Mizoribine (6.5) is a closely related drug which inhibits nucleotide synthesis, preferentially in lymphocytes. 

Mechanism of Action Selectively inhibits inosine monophosphate dehydrogenase in the de novo pathway of purine synthesis, producing potent cytostatic effects on T and B lymphocytes... 

C. Synthesis of inosine monophosphate, the "parent" purine nucleotide... 

Mechanism of Action. Mycophenolate mofetil inhibits a specific enzyme (inosine monophosphate dehydrogenase) that is responsible for the synthesis of DNA precursors in T and B lymphocytes.39 50 Because these lymphocytes cannot synthesize adequate amounts of DNA, their ability to replicate and proliferate is impaired, thus blunting the immune response. This drug may also inhibit lymphocyte attraction and adhesion to the vascular endothelium, thereby impairing the lymphocytes ability to migrate to the site of the foreign (transplanted) tissues and to infiltrate from the bloodstream into these tissues.50... 

Purine synthesis uses a PRPP handle where the ring is assembled to make a 5 NMP, inosine monophosphate (IMP). 

The synthesis of the purine ring is considerably more complex than pyrimidine synthesis. Starting with P-Rib-PP, inosine monophosphate (IMP) is formed in 10 steps (Fig. 15-16). The overall reaction is... 

Inosine Monophosphate Dehydrogenase. Proliferative cells such as lymphocytes have high demands for the rapid supply of nucleotides to support DNA and RNA synthesis, as do viruses during their proliferative phase. The first dedicated step in the de novo biosynthesis of guanine nucleotides is conversion of inosinate to XMP, catalyzed by inosine monophosphate dehydrogenase (IMPDH). 

The pathway to purine synthesis is rather long. Parts of the purine molecule are from glycine, tetrahydrofo-late (a one-carbon donor), glutamine, CO and aspartate (fig. 5.4) (B-3). This pathway enters the purine section of the DNA Funhouse at IMP" (Inosine monophosphate), at the ground level. The body can avoid part of the long... 

Mycophenolate mofetil is the 2-moiphohnoethyl ester of mycophenolic acid (MPA). It is a prodrug that is rapidly hydrolyzed to the active form, mycophenolic acid. Mycophenolic acid is a selective, uncompetitive and reversible inhibitor of inosine monophosphate dehydrogenase (IMPDH). IMPDH is an important enzyme in the de novo pathway of purine nucleotide synthesis. This pathway is very important in B and T lymphocytes for proliferation. Other cells can use salvage pathways. Therefore MPA inhibits lymphocyte proliferation and functions. The mofetil ester is first converted to MPA which then is metabolized to an inactive glucuronide (Alhson and Eugui, 2000). MPA has a half-hfe of about 16 hours (Fulton and Markham, 1996). 

FIGURE 9.11 Conversion of inosine monophosphate to adenosine monophosphate and guanos-ine monophosphate. Aspartate donates an amino group in the s)mthesis of AMP. Glutamine donates an amino group in the synthesis of GMP. Folate is not used in these steps of purine metabolism. 

This in situ generation of enamines and subsequent Heck cyclization to afford indoles has been adopted by several groups for the synthesis of indoles (and azaindoles) from 2-chloroanilines [337], tricyclic inhibitors of 5 -inosine monophosphate dehydrogenase [145], medium-ring fused indoles [338], and tetrahydrocarbazole in an Organic Synthesis preparation [339]. Some mechanistic insights have been offered [340]. The use of aryl-propynamides and rV-alkynyl-2-haloanilides under Heck conditions affords oxindoles [341] and 2-aminomdoles [342], respectively. An example of the latter is illustrated for 323 to 324. 

Mycophenolate mofetil is an immnnosnppressant that can snppress lymphocyte prohferation. It inhibits inosine monophosphate dehydrogenase, which is pivotal in de novo pnrine synthesis in lymphocytes. Mycophenolate mofetil, 1 to 3 g/day, has been reported to have steroid-sparing effects in patients with minimal-change disease as well as other forms of glomemlonephritis. ... 

HGPRT Hypoxanthine-guanine phosphoribosyltransferase the enzyme that catalyzes the synthesis of inosine monophosphate (IMP) and guano-sine monophosphate (GMP) from hypoxanthine and guanine, respectively. It makes up part of the purine salvage pathway, a way of recycling purine bases back to the nucleotides. 

The substrate for this reaction, ct-D-ribose-5-phosphate, is a product of the pentose phosphate pathway.) Figure 14.24 illustrates the initial phase in the pathway by which PRPP is converted to inosine monophosphate (inosinate), the first purine nucleotide. The process begins with the displacement of the pyrophosphate group of PRPP by the amide nitrogen of glutamine in a reaction catalyzed by glutamine PRPP amidotransferase. This reaction is the committed step in purine synthesis. The product formed is 5-phospho-/3-D-ribosylamine. 

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