Why is de novo biosynthesis of purines markedly elevated in patients with adeficiency in hypoxanthine-guanine phosphoribosyl transferase (HGPRT)?5-Fluoruracil is converted to methotrexate by a DPD deficiency, leadingto increased purine biosynthesis.HGPRT deficiency prevents purine salvage, leading to increased purinebiosynthesis to make up for it.HGPRT increases pyrimidine salvage and thereby increases purinebiosynthesis as a result.Increased purine biosynthesis is the result of ATP hydrolysis during theproduction of cyclic AMP.

HGPRT is an important enzyme in the recycling of building blocks of nucleic acids like DNA or RNA.…

Answered: Why is de novo biosynthesis of purines…

Biochemistry

9th Edition

ISBN:9781319114671

Author:Lubert Stryer, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto Jr.

Publisher:Lubert Stryer, Jeremy M. Berg, John L. Tymoczko, Gregory J. Gatto Jr.

Chapter1: Biochemistry: An Evolving Science

Section: Chapter Questions

Problem 1P

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6-Mercaptopurine , after its conversion to the corresponding nucleotide through salvage reactions, is a potent competitive inhibitor of IMP in the pathways for AMP and GMP biosynthesis. It is therefore a clinically useful anticancer agent. The chemotherapeutic effectiveness of 6 mercaptopurine is enhanced when it is administered with allopurinol. Explain the mechanism of this enhancement.
Why Phenylmethylsulfonyl fluoride (PMSF, shown in Fig.) does not inhibit aspartate protease as potent as serine protease?
Cells defective in thymidylate synthase are able to undergo cell division if methotrexate and thymidine are both provided; however, cells with fully functional thymidylate synthase cannot divide under these same culture conditions. What is the biochemical basis for this observation?
The enzymatic activity of PFK1 is generally measured by set- ting up a coupled enzyme assay system whereby aldolase, triose phos- phate isomerase, and glycerol-3-phosphate dehydrogenase are added to the assay mixture. For the latter enzyme, NADH is added and its change in concentration is readily monitored at 340 nm. Write the chain of reactions catalyzed by these enzymes using structural formulas, label substrates and products, and explain why the coupled en- zyme assay system leads to oxidation of NADH. While the chain of reac- tions is similar to those in glycolysis, there is a critical difference because of the dehydrogenase enzyme. Describe how this enzyme causes the chain of reactions to differ from those in glycolysis.
Thiopurine S-methyltransferase (TPMT) is an enzyme that is responsible for the metabolism of the drugs azathioprine and 6-mercaptopurine, which are used to treat acute lymphoblastic leukemia and inflammatory bowel disease. Metabolism by TPMT reduces the bioavailability of the drugs. In addition to the thiopurine substrates, TPMT also binds S-adenosyl methionine as a cofactor. TPMT is a highly polymorphic enzyme; almost 30 variants are known to be expressed in humans, with most of the variants possessing lower enzymatic activity than the wild-type protein (TPMTwt). Despite having substitutions remote from the active site, TPMT*2 (an A80P variant) and TPMT*5 (an L49S variant) have enzyme activities of 47% and 14% relative to TPMTwt at 18°C, respectively. Two techniques were used to understand the relationships between enzymatic activity and protein stability. Circular dichroism (CD) spectroscopy measures the differential absorption of left and right-circularly polarized light and is used…
Hydroxyurea has been shown to increase the expression of fetal hemoglobin in adult red blood cells, by a mechanism that remains unclear. Explain why hydroxyurea can be a useful therapy for patients with sickle-cell anemia.
As stated in the text, mammalian cells can become resistant to the lethal action of methotrexate by the selective survival of cells con- taining increases in dihydrofolate reductase gene copy number so that intracellular levels of the enzyme become very high. What other biochemical or genetic changes in cells could cause them to become resistant to methotrexate?
Dihydrofolate reductase (DHFR) is an enzyme that reduces 7,8-dihydrofolate (DHF) to 5,6,7,8- tetrahydrofolate, a step in the biosynthesis of thymidine. Methotrexate (MTX) a structural analogue of dihydrofolate, inhibits this enzyme. MTX has been used in cancer therapies because the inhibition of DHFR restricts thymidine production required for cell division. In the absence of thymidine the cancerous cells cannot multiply. Using the following data of DHFR activity in the presence of MTX, i) Determine the inhibition mechanism of MTX and the maximum reaction rate. If Km for DHFR is 0.100 uM, what is K; ? ii) [DHF](MM) Rate w/200 nM Rate w/50 nM MTX (mMs-¹) Rate w/100 nM MTX MTX (mMs ¹) (mMs ¹) 3 7.38 5.56 3.72 6 8.84 7.38 5.55 9 9.46 8.29 6.65 12 9.79 8.84 7.38
Gerhart and Pardee measured ATCase activity in the presence of a variety of purine and pyrimidine derivatives. Their results are presented in Table 2. What compound(s) were the most effective inhibitors? activators? Explain the significance of the metabolites that served as inhibitors or activators in the context of the biosynthetic pathway presented in Figure 1. Table 2: Effect of nitrogen bases, nucleosides and nucleotides on ATCase activity. *Indicates stimulation. (Based on Gerhart and Pardee, 1962.) Compound Inhibition, % (Conc = 2 mm) Cytosine 0 Cytidine 24 CMP 38 dCMP 48 CTP 86 dCTP 88 UTP 8 GTP 35 dGTP 31 -180* -162* ATP dATP
When hyaluronan synthase from Pasteurella multocida was expressed in E. coli, the bacteria spun out a capsule of hyaluronan. This reaction was analyzed using purified membrane fragments containing the hyaluronan synthase, a radio-labeled tetrasaccharide acceptor (Part A), along with the activated forms of the sugar subunits: UDP-N-acetylglucosamine and UDP-glucuronic acid. In short incubations with the complete mixture, the tetrasaccharide primer elongated by several units, although only odd-numbered chains were visible (Part B lane 2). If one or both activated sugars were left out, the results shown in lanes 3-5 (Part B) were obtained. Why do you suppose that only odd-number chains are visible in your assay? (A) ACCEPTOR nonreducing end HO- HO OH COO glucuronic acid (GICUA) HO- CH3 T C=O I NH CH₂ OH N-acetylglucosamine (GlcNAc) COO но- HO OH OH I CH₂ reducing end NH C=O CH3 Choose one: O A. Synthase adds GlcNAc much more slowly than it adds GICUA. O B. One of the monosaccharide…
In the salvage of purines, hypoxanthine-guanine phosphoribosyltransferase (HGPRT) is responsible for which of the following processes? Conversion of hypoxanthine to xanthine Conversion of adenine to adenosine monophosphate (AMP) Conversion of guanine to guanosine monophosphate (GMP) Conversion of inosine monophosphate to inosine
What is the logic behind high levels of arginine positivelyregulating N-acetylglutamate synthase?

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