Nucleotide you ii.pptxsheikh abdul wadood haneef

Editor's Notes

• #7: Adenine and guanine are found in both DNA and RNA. Hypoxanthine and xanthine are not incorporated into the nucleic acids as they are being synthesized but are important intermediates in the synthesis and degradation of the purine nucleotides. Cytosine is found in both DNA and RNA. Uracil is found only in RNA. Thymine is normally found in DNA. Sometimes tRNA will contain some thymine as well as uracil.
• #8: Ribonucleoside NAD+, NADP+. In pyrimidine NucleotideMetabolism OVERVIEW Ribonuclosid and deoxyribonucleoside phosphates (nucleotides) are essential for all cells. Without them, neither DNA nor RNA can be produced and, therefore, proteins cannot be synthesized or cells proliferate. Nucleotides also serve as carriers of activated intermediates in the synthesis of some carbohydrates, lipids, and proteins, and are structural components of several essential coenzymes, for example, coenzyme A, FAD, NAD+,NADP+ and Nucleotides, such as cyclic AMP (cAMP) and cyclic GMP (cGMP), serve as second messengers in signal transduction pathways. In addition, nucleotides play an important role as "energy currency" in the cell. Finally, nucleotides are important regulatory compounds for many of the pathways of intermediary metabolism, inhibiting or activating key enzymes. The purine and prymidin bases found in nucleotides can be synthesized de novo, or can be obtained through salvage pathways that allow the reuse of the preformed bases resulting from normal cell turnover or from the diet.
• #16: All purine degradation leads to uric acid (but it might not stop there) Ingested nucleic acids are degraded to nucleotides by pancreatic nucleases, and intestinal phosphodiesterases in the intestine Group-specific nucleotidases and non-specific phosphatases degrade nucleotides into nucleosides Direct absorption of nucleosides Further degradation Nucleoside + H2O  base + ribose (nucleosidase) Nucleoside + Pi  base + r-1-phosphate (n. phosphorylase) NOTE: MOST INGESTED NUCLEIC ACIDS ARE DEGRADED AND EXCRETED.
• #17: DNA synthesis and its precursor nucleotides are coordinately regulated with the cell cycle progression before and during the S-phase and inhibitors of nucleotide synthesis are utilized to inhibit cell proliferation as in cancer treatment and immunosuppression for organ transplantation patients. Nucleotides are not only essential for DNA and RNA synthesis, but also, for energy metabolism (e.g., ATP and GTP), coenzyme formation (e.g., NAD and FAD), synthesis of active intermediates (e.g., Sadenosylmethionine); signal transduction (e.g., cAMP and cGMP); allosteric enzyme regulation (e.g., ATP and cAMP); and in their modified form are used as chemotherapy for cancer, immunosuppression and viral infection.
• #18: High PRPP – denovo Low PRPP – salvage of purine synthesis
• #19: 3aas for purine synthesis; Glycine Glutamate and Aspartate And also co2 and THF
• #22: A. The cell maintains an important pool of purine nucleotides for synthesis of coenzymes and precursors for DNA and RNA and to support reactions that are coupled to ATP hydrolysis. B. Purine nucleotides can be synthesized de novo from amphibolic or dual-purpose intermediates, which may be derived either from anabolic or catabolic pathways.
• #23: Amidophosphoribosyl transferase is an important regulatory enzyme in purine biosynthesis. It is strongly inhibited by the end products IMP, AMP, and GMP. This type of inhibition is called FEEDBACK INHIBITION.
• #24: 1. Ribose 5-phosphate derived from the pentose phosphate pathway or from dietary sources is the starting material that eventually gives rise to inosine monophosphate (IMP) (Figure 10–1). 2. The overall strategy is to build the carbon-nitrogen skeleton of a purine ring system in a 12-step process directly on the sugar-phosphate starting material. a. The first step creates the multi-purpose intermediate 5-phosphoribosyl-1- pyrophosphate (PRPP). b. Then, PRPP glutamyl amidotransferase, the key regulatory enzyme, acts upon PRPP to begin making the purine ring; this is the committed step of purine synthesis.
• #25: c. Carbons are added to the growing ring in several ways: (1) By one-carbon transfer by enzymes that use tetrahydrofolate (THF) coenzymes. (2) By incorporation of glycine in the structure. (3) By addition of CO2 in the form of bicarbonate.
• #26: d. Nitrogens are added by the following: (1) Aminotransfer reactions with glutamine as donor. (2) In a two-step mechanism with aspartic acid as donor.
• #34: Inhibitors of human purine synthesis are extremely toxicto tissues, especially to developing structures such as in a fetus, or to cell types that normally replicate rapidly, including those of bone marrow, skin, gastrointestinal tract, immune system, or hair follicles. Nucleotide Triphosphate Inhibitors Historically there have been several approaches in developing cancer therapeutics that bear chemical similarity to the various “building blocks” of nucleic acids and inhibit the formation of functional nucleotide triphosphates needed to synthesize either DNA or RNA. Many of these agents have been labeled “antimetabolites” because of their structural similarities to naturally occurring metabolites (Daher et al. 1994; Pizzorno et al. 2003). These include the antifolates (e.g., methotrexate), pyrimidines like 5-Fluorouracil (5-FU), and purines like 6- mercaptopurine and 6-thioguanine (Fig. 2). Other drugs like hydroxyurea are not “antimetabolites” from the perspective of mimicking nucleic acid “building blocks”, but have unique inhibitory effects on important steps in the conversion of nucleotides (Fig. 2-J and K). Some of these agents like hydroxyurea are relatively pure S-phase inhibitors, while others like 5-FU have activities extending beyond S-phase itself. As a class, all of the agents inhibit DNA synthesis and affect the S-phase of the cell cycle. Thus rapidly growing cancers theoretically should be potentially the most responsive. They also share toxicities toward the most rapidly growing normal “host” cells (e.g., hematopoietic cells - white blood cells, red Chapter 26, Pharmacological agents that target DNA replication, p. 3 of 28 blood cells, and platelets; gastrointestinal mucosal cells and hair) such that common side effects are produced (e.g. myelosuppression, anemia, thrombocytopenia, diarrhea, and
• #35: e. Conversion of the main product of de novo synthesis, IMP, to GMP or AMP, occurs in two reactions, both of which are inhibited by feedback regulation by the end products. f. Overall flux through the purine synthetic pathways is regulated primarily by feedback inhibition of PRPP glutamyl amidotransferase, by IMP, AMP, and GMP (Figure 10–2).
• #36: Cross-regulation Is the only time in biochemistry, we use ATP to synthesise GMP and vice versaAfter the branch point, addition of the amino group of aspartate onto IMP in two reactions activated by the 3rd key regulatory adenylosuccinate synthetase and adenylosuccinase, respectively release fumarate and gives AMP. IMP dehydrogenation into XMP (xanthosine monophosphate) is activated by the 4th key regulatory IMP dehydrogenase. XMP transamidination by glutamine to give GMP is activated by the transamidinase (or GMP synthetase). IMP conversion into AMP is activated by GTP as energy deriver, or into GMP is activated by ATP as energy deriver . through the aforementioned two distinct reaction pathways. Such inter-dependence of AMP on GTP and GMP on ATP provides controlling tool to balance AMP and GMP ratio to near equivalence. The substrate-specific nucleoside monophosphate and the non-specific nucleoside diphosphate kinases convert AMP into ADP and ATP; and, GMP into GDP and GTP, respectively.
• #37: 6-Mercaptopurine (6-MP): 6-MP is a hypoxanthine derivative antimetabolite (see Fig. 2F) whose metabolites inhibit endogenous de novo purine synthesis at several steps (Fig. 2G) (Pizzorno et al. 2003). One of the most important metabolic activation is the formation of the nucleotide 6-MP ribose-5’- Chapter 26, Pharmacological agents that target DNA replication, p. 5 of 28 phosphate also known as thioinosine monophosphate (TIMP) in the presence phosphoribosylpyrophosphate (PRPP) and the enzyme hypoxanthine –guanine phosphoribosyltransferase (HGPRT). Once formed TIMP can inhibit several steps in de novo purine synthesis. The most important of these inhibited steps is the formation of phosphoribosylamine from PRPP and glutamine (Fig. 2G). This step however is under feedback control being naturally inhibited by adenine or guanine nucleotides (AMP or GMP). TIMP causes a pseudo feedback inhibition mimicking the effect of AMP or GMP. TIMP is thought to inhibit de novo purine synthesis at two other steps (Fig. 2G): the conversion of IMP to GMP and the conversion of GMP to AMP. 6-MP is not taken up to any great extent into nucleic acid itself but rather affects the synthesis of purine nucleotides needed for both RNA and DNA synthesis. Thus, while S-phase may be primarily affected, 6- MP is not a pure S-phase inhibitor. 6-MP is used mainly in acute leukemias. As might be expected because of the affect mainly on rapidly proliferating cells, toxicities are seen in rapidly growing normal host cells in particular hematopoietic cells.
• #38: 6-Thioguanine (6-TG): Although structurally very similar to 6-MP (see Fig. 2H), 6-TG has a very different mechanism of action from 6-MP (Pizzorno et al. 2003). As is shown in Fig. 2I, 6-TG is metabolized to 6-TG-deoxyribonucleotide triphosphate (6-TdGTP), which can then be incorporated into DNA in place of dGTP. Futile mismatch repair and DNA fragmentation occur as the cell attempts to excise 6-TG from the DNA. As a result 6-TG affects S-phase cells primarily. 6-TG is mainly used in acute leukemias with toxicities being observed in rapidly growing host tissues like hematopoietic and mucosal cells.
• #39: Coupling of Reactions Hydrolyzing a phosphate from ATP is relatively easy G°’= -30.5 kJ/mol If endergonic reaction released energy into cell as heat energy, wouldn’t be useful Must be coupled to an exergonic reaction When ATP is a reactant: Part of the ATP can be transferred to an acceptor: Pi, PPi, adenyl, or adenosinyl group ATP hydrolysis can drive an otherwise unfavorable reaction (synthetase; “energase”)
• #40: The active forms of nucleotides in biosynthesis and energy conversions are di-and tri-phosphates Nucleoside diphosphates (NDP) are synthesized from the corresponding nucleoside monophosphates (NMP) by base-specific nucleoside monophosphate kinases (Figure 22.9). [Note: These kinases do not discriminate between ribose or deoxyribose in the substrate.] ATP is generally the source of the transferred phosphate, because it is present in higher concentrations than the other nucleoside triphosphates. Adenylate kinase is particularly active in liver and muscle, where the turnover of energy from ATP is high. function is to maintain an equilibrium among AMP, ADP, and ATP. Nucleoside diphosphates and triphosphates are interconverted by nucleoside diphosphate enzyme that, unlike the monophosphate kinases, has broad specificity.
• #43: GTP is involved in AMP synthesis and ATP is involved in GMP synthesis (reciprocal control of production) PRPP is a biosynthetically “central” molecule (why?) ADP/GDP levels – negative feedback on Ribose Phosphate Pyrophosphokinase Rate of AMP production increases with increasing concentrations of GTP; rate of GMP production increases with increasing concentrations of ATP Amidophosphoribosyl transferase is activated by PRPP levels APRT activity has negative feedback at two sites ATP, ADP, AMP bound at one site GTP,GDP AND GMP bound at the other site Above the level of IMP production: Independent control Synergistic control Feedforward activation by PRPP Below level of IMP production Reciprocal control Total amounts of purine nucleotides controlled Relative amounts of ATP, GTP controlled
• #44: Stimulus – low PRPP Salvage pathway recycles purine bases and nucleosides into nucleotide. It is the sole source for purine nucleotides in some parasites (e.g., Mycoplasma, Borrelia, and Chlamydia). It is a significant source of purine nucleotides because hypoxanthine accumulation inhibits the de novo synthesis at the 2nd rate limiting amidotransferase step. In mammals, every cell is capable to salvage purines - particularly lymphocytes - through the following two mechanisms:
• #46: i. Single Step Direct Conversion by phosphoribosylation activated by adenosine phosphoribosyltransferase (APRT) giving rise to AMP and by hypoxanthine-guanine phosphoribosyltransferase (HGPRT) that gives either IMP or GMP. Accumulation of AMP inhibits APRT and accumulation of GMP inhibits HGPRT; see the reaction below.
• #47: Salvage is needed to maintain the purine pool (biosynthesis is not completely adequate, especially in neural tissue) Hypoxanthine-guanine phosphoribosyltransferase (HGPRT) Hypoxanthine + PRPP IMP + Ppi Guanine + PRPP GMP + Ppi Lack of HGPRT leads to Lesch-Nyhan syndrome. Lack of enzyme leads to overproduction of purines which are metabolized to uric acid, which damages cells
• #49: disorder associated with a virtually complete deficiency of HPRT. This deficiency results in an inability to salvage hypoxanthine or guanine, from which excessive amounts of uric acid are produced. addition, the lack of this salvage pathway causes increased PRPP levels and decreased and GMP levels. As a result, glutamine:phosphoribosylpyrophosphate amidotransferase (the committed step in purine synthesis) has excess substrate and decreased inhibitors available, and de novo purine synthesis is increased. The combination of decreased purine reutilization and increased purine synthesis results in the production of large amounts of uric acid, making the Lesch-Nyhan syndrome a severe, heritable form of gout. Patients with Lesch-Nyhan syndrome tend to produce urate kidney stones. addition, characteristic neurologic features of the disorder include self-mutilation (Figure 22.11) and involuntary movements.
• #52: The enzyme has allosterically regulated binding sites for all nucleotides (oxy- and deoxy-) to modulate the substrate specificity and the overall reaction rate that ensures balanced production of deoxyribonucleotides for synthesis of DNA. There are two major allosteric sites; one controls the overall activity of the enzyme, whereas, the other determines the substrate specificity of the enzyme. ATP binds the overall activity site to activate the enzyme, whereas, dATP binding to this site inhibits the enzyme; detailed as follows. For the substrate specificity, ATP binding to the substrate site activates the reduction of pyrimidines (CDP and UDP) to form dCDP and dUDP. The dUDP is converted into dTTP. Accumulated dTTP binds to the substrate site and induces the reduction of GDP. Accumulated dGTP displaces dTTP to allow ADP to be reduced to dADP. Accumulated dATP inhibits the overall activity of the enzyme. The enzyme is inhibitable by the anticancer hydroxyurea.
• #53: Regulation of deoxyribonucleotide synthesis Ribonucleotide reductase is responsible for maintaining a balanced supply of the deoxyribonucleotides required for DNA synthesis. To achieve this, the regulation of the enzyme is complex. addition to the single active site, there are two sites on the enzyme involved in regulating its activity (Figure 22.13). Activity site: The binding of dATP to an allosteric site (known as the activity site) on the enzyme inhibits the overall catalytic activity of the enzyme and, therefore, prevents the reduction of any of the four nucleoside diphosphates. This effectively prevents DNA synthesis, and explains the toxicity of increased levels of dATP seen in conditions such as adenosine deaminase deficiency (see p. 299). Substrate specificity site: The binding of nucleoside triphosphates to an additional allosteric site (known as the substrate specificity site) on the enzyme regulates substrate specificity, causing an increase in the conversion of different species of ribonucleotides to deoxyribonucleotides as they are required for DNA synthesis.
• #63: Channeling: enzymes 1, 2, and 3 on same chain; 5 and 6 on same chain
• #64: OMP DECARBOXYLASE : THE MOST CATALYTICALLY PROFICIENT ENZYME FINAL REACTION OF PYRIMIDINE PATHWAY ANOTHER MECHANISM FOR DECARBOXYLATION A HIGH ENERGY CARBANION INTERMEDIATE NOT NEEDED NO COFACTORS NEEDED ! SOME OF THE BINDING ENERGY BETWEEN OMP AND THE ACTIVE SITE IS USED TO STABILIZE THE TRANSITION STATE “PREFERENTIAL TRANSITION STATE BINDING”
• #65: Pyrimidine Antimetabolites5-Fluorouracil (5-FU) also blocks thymidylate synthesis as MTX, but works specifically on TS (Fig. 2D-E). TS converts deoxyuridine monophosphate (dUMP) to thymidine monophosphate (dTMP). TS is inhibited non-competitively by the 5-FU-deoxyuridine Chapter 26, Pharmacological agents that target DNA replication, p. 4 of 28 monophosphate (5-fluorodeoxyuridylate; FdUMP) (Fig. 2E). The resultant depletion of dTMP inhibits DNA synthesis and cell division. In addition, the accumulation of dUMP as well as the FdUMP pool formed from 5-FU can be incorporated into DNA. The repair enzymes (e.g., uracil glycosylase) can remove the incorporated uracil or 5-FU from the DNA resulting in DNA breaks, which further contribute to the S-phase directed cytotoxicity of 5- FU. Lastly, the ribonucleotide of 5-FU (FUMP) can be mis-incorporated into RNA. Because RNA dysfunction is not cell cycle specific, the resultant cytotoxicity effect is not confined only to the S-phase (Daher et al. 1994; Pizzorno et al. 2003). There have been many attempts over the years to design a better drug than 5-FU. In particular has been the desire to develop a 5-FU that could be administered orally, motivated by studies demonstrating that prolonged infusion of 5-FU had therapeutic advantages. A number of oral fluoropyrimidines have been synthesized (Diasio 1999). Capecitabine is the only oral 5-FU drug approved for use in the US, although several other analogs or prodrugs are available elsewhere. This prodrug has an added biochemical benefit in that the final step of activation to 5-FU occurs within the tumor thereby lessening release of 5-FU into the general circulation, where it potentially can affect sensitive host tissues like bone marrow, gastrointestinal mucosa, or the integument (skin, hair, and mucosal membranes). 5-FU has enjoyed extensive use in the treatment of a number of solid malignancies over the past 45 yrs (Table VIII). Today it is the major agent for advanced colorectal cancer and continues to be used in other gastrointestinal malignancies, such as stomach, esophageal and pancreatic cancer. 5-FU is also used in advanced breast and skin cancers. The deoxyribonucleoside of 5-FU, 5-fluorodeoxyuridine (FUDR or FdUrd) has been used for hepatic arterial infusion to treat liver metastases particularly from colorectal cancer. As noted above, Capecitabine has now been approved for advanced breast cancer and for both advanced and adjuvant treatment of colorectal cancer.: 5-Fluorouracil and Related Drugs
• #67: The synthesis is largely controlled through product feedback allosteric regulation. The key regulatory carbamoyl phosphate synthetase II in humans is inhibited by UTP (and by purine nucleotides) and activated by PRPP. The sensitivity to activating effect of PRPP ismaximized close to S-phase of the cell cycle, where sensitivity to the inhibitory effect of UTP is minimized; i.e., the enzyme is more readily activated. The opposite happens at the end of the S-phase. This alteration in the sensitivity of the enzyme is due to its activating phosphorylation by the Mitogen Activated Protein Kinase (MAPK) in cells committed to cell division. But phosphorylation at a different site by the cAMP-dependent protein kinase makes carbamoyl phosphate synthetase II more readily inhibitable. CTP inhibits and ATP activates aspartate transcarbamoylase leading to a strict balance between thymine and cytosine nucleotides. This also reflects coordinate regulation of purine and pyrimidine biosynthesis mole for mole and accumulation of both type of nucleotides allosterically inhibit PRPP synthase, a key regulatory step for both. Coordinated repression and derepression control the first 3 steps into dihydroorotic acid and 5th and 6th steps into UMP. The anticancer 6-azauridine and allopurinol as alternative substrates inhibit orotidylate decarboxylase.
• #69: INHIBITORS OF dTMP SYNTHESIS AS ANTICANCER AGENTS • Several drugs that interfere with production of dTMP by blocking the reaction catalyzed by thymidylate synthetase are inhibitors of DNA synthesis and cell proliferation. • Methotrexate is a folate analog that acts as a potent competitive inhibitor of dihydrofolate reductase, causing a decreased supply of THF coenzymes needed by thymidylate synthetase. • The thymine analog 5-fluorouracil (5-FU) is converted to 5-fluoro-dUMP, which acts as a suicide inhibitor of thymidylate synthetase.
• #72: Dietary uptake of purine and pyrimidine bases is minimal. The diet contains nucleic acids and the exocrine pancreas secretes deoxyribonuclease and ribonuclease, along with the proteolytic and lipolytic enzymes. This enables digested nucleic acids to be converted to nucleotides. The intestinal epithelial cells contain alkaline phosphatase activity, which will convert nucleotides to nucleosides. Other enzymes within the epithelial cells tend to metabolize the nucleosides to uric acid, or to salvage them for their own needs. Dietary uptake of purine and pyrimidine bases is minimal. The diet contains nucleic acids and the exocrine pancreas secretes deoxyribonuclease and ribonuclease, along with the proteolytic and lipolytic enzymes. This enables digested nucleic acids to be converted to nucleotides. The intestinal epithelial cells contain alkaline phosphatase activity, which will convert nucleotides to nucleosides. Other enzymes within the epithelial cells tend to metabolize the nucleosides to uric acid, or to salvage them for their own needs. Approximately 5% of ingested nucleotides will make it into the circulation, either as the free base or as a nucleoside. Because of the minimal dietary uptake of these important molecules, de novo synthesis of purines and pyrimidines is required.
• #76: Nucleotides broken into nucleosides by action of 5’-nucleotidase (hydrolysis reactions) Purine nucleoside phosphorylase (PNP) Inosine  Hypoxanthine Xanthosine  Xanthine Guanosine  Guanine Ribose-1-phosphate splits off Can be isomerized to ribose-5-phosphate Adenosine is deaminated to Inosine (ADA)
• #77: About 80% of uric acid formed in the body is excreted in urine. The remaining is probably excreted in the bile. The amount of uric acid excreted in the urine varies between 0.5 - 0.6 gm/day. It is mainly in the form of uric acid . The uric acid excretion is approximately halved on a purine-free diet, . Thus, controlling the dietary supply of purines helps preventing hyperuricemia.
• #78: In lower primates and other mammals, the copper-dependent uricase enzyme converts uric acid to allantoin by oxidative decarboxylation. In birds and reptiles, uric acid is the chief end product of not only purines but also protein nitrogen.
• #81: CLASSIFICATION — Persistent hyperuricemia is a common biochemical abnormality that results from excessive urate production and/or diminished renal uric acid excretion. (See "Uric acid balance".) Persistent hyperuricemia can be divided into two categories: Primary hyperuricemia, which usually lasts indefinitely, describes urate saturation arising in the absence of coexisting diseases or drugs that alter uric acid production or excretion. Secondary hyperuricemia refers to excessive urate production (table 1) or diminished renal clearance (table 2) that is the result of another disease, drug, dietary product, or toxin. CLINICAL SYNDROMES — The three classic stages in the natural history of progressive urate crystal deposition disease (gout) are: Acute gouty arthritis Intercritical (or interval) gout Chronic recurrent and tophaceous gout
• #82: Urolithiasis - stones in urinary tract: the formation or presence of stony masses in the urinary tract, or the medical condition resulting from thisMicrosoft® Encarta® 2009. © 1993-2008 Microsoft Corporation. All rights reserved.
• #84: fluid lubricating joints: a clear viscous fluid that lubricates the linings of joints and the sheaths of tendonsMicrosoft® Encarta® 2009. © 1993-2008 Microsoft Corporation. All rights reserved.
• #86: Colchicine - poisonous plant extract: a poisonous extract of autumn crocus plants. Use: to inhibit cell division and cause chromosome doubling in plants, to treat gout.Microsoft® Encarta® 2009. © 1993-2008 Microsoft Corporation. All rights reserved.
• #87: INTRODUCTION — Pharmacologic modalities employed in the treatment of gout can be classified as antiinflammatory, prophylactic, and antihyperuricemic. These designations reflect the three distinctive aims of treatment: Antiinflammatory therapy for prompt and safe termination of the acute arthritic attack Antiinflammatory prophylaxis for prevention of recurrences of acute gouty arthritis Antihyperuricemic (urate-lowering) therapy for prevention and reversal of the consequences of urate crystal deposition in joints (gouty arthropathy), urinary tract (nephrolithiasis), renal interstitium (rarely producing renal failure due to urate nephropathy), and tissues and parenchymal organs (tophi) Dietary control by avoidance of nucleic acid-rich diets, e.g., liver and meat particularly of old animals and birds is recommended. Dairy products, eggs and meat of young animals are more suitable.
• #88: PATHOGENESIS — SCID is a syndrome caused by mutations in different genes whose products are crucial for the development and function of both T and B cells [2]. In some cases, the molecular defect prevents only T cell function, while B cells are normal. However, since B cells require signals from T cells to produce antibody, serious T cell dysfunction precludes effective humoral immunity. Natural killer (NK) cells, a non-T, non-B lymphocyte subset exhibiting cytotoxic activities, develop via a pathway distinct from B and T cells. NK cells are present in approximately 50 percent of patients with SCID and may provide a degree of protection against bacterial and viral infections in these patients. Determining the presence or absence of NK cells is also helpful in classifying patients with SCID.
• #89: IN-CLASS QUESTION: EXPLAIN THE BIOCHEMISTRY THAT RESULTS WHEN A PERSON HAS ADA DEFICIENCY (HINT: LYMPHOID TISSUE IS VERY ACTIVE IN DEOXYADENOSINE PHOSPHORYLATION)
• #95: Orotic acidosis and orotic aciduria types I and II are very rare genetic condition accompanied with poor growth and hypochromic megaloplastic anemia with defective maturation of red cells and leukopenia. They are treatable by supplementing cytidine or uridine that replenishes the deficiency by being converted into UMP. This also feedback inhibits carbamoyl phosphate synthetase II and oroticacid synthesis to ease the acidosis. Allopurinol and azauridine cause orotic aciduria because their catabolites inhibit OMP decarboxylase.