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Home , Adenylosuccinate, Carbamoyl phosphate, Urate oxidase

BCH 304 STUDY QUESTIONS & ANSWERS Biochemist Oh!Best

Q1- What is the difference between De-novo synthesis of and nucleotide synthesis by the salvage pathways? Answer: In De-novo synthesis, the are synthesized from simpler precursor compounds, in essence from scratch. In salvage pathways, preformed bases are recovered and attached to ribose.

Q2- Identify the sources of the atoms of and ring during their De-novo synthesis. Answer: In purines:

i. Glycine provides C4, C5 and N7 5 10 ii. N , N -Formyl tetrahydrofolate (THF) provides C2 and C8 iii. provide N3 and N9 iv. CO2 provide C6 v. Aspartate provides N1

In pyrimidines:

Glutamine CO2

i. Glutamine provides N3 ii. Aspartic acid provides C4, C5, C6 and N1 iii. Carbon dioxide (CO2) provides C2

Q3- Create a match (a) Excessive urate___ Spina bifida (b) Lack of adenosine deaminase___ Precursor to both ATP and GTP (c) Lack of HGPRT___ (d) Carbamoyl phosphate___ Deoxynucleotide synthesis (e) Inosinate___ UTP (f) Ribonucleotide reductase___ Lesch-Nyhan disease (g) Lack of folic acid___ Immunodeficiency (h) Glutamine phosphoribosyl transferase___ (i) Single ring___ (j) Bicyclic ring___ First step in pyrimidine synthesis (k) Precursor to CTP___ Committed step in purine synthesis

Answer: (a) Excessive urate___ Gout (b) Lack of adenosine deaminase___ Immunodeficiency (c) Lack of HGPRT___ Lesch-Nyhan disease BCH 304 STUDY QUESTIONS & ANSWERS Biochemist Oh!Best

(d) Carbamoyl phosphate___ First step in pyrimidine synthesis (e) Inosinate___ Precursor to both ATP and GTP (f) Ribonucleotide reductase___ Deoxynucleotide (g) Lack of folic acid___ Spina bifida (h) Glutamine phosphoribosyl transferase___ Committed step in purine synthesis (i) Single ring___ Pyrimidine (j) Bicyclic ring___ Purine (k) Precursor to CTP___ UTP

Q4- Azaserine (an analog of glutamine) inhibits the amido . Identify the intermediate of purine that would accumulate in cells treated with Azaserine. Answer: The intermediate that would be accumulated in the cells are PRPP and formyl glycinamide ribonucleotide (FGAR).

Q5- Discuss the inhibitory action of sulfanilamide and related sulfa drugs in growth in relation to nucleotide biosynthesis. Answer: There is a deficiency of N10-formyltetrahydrofolate. Sulfanilamide inhibits the synthesis of folate by acting as an analog of p-aminobenzoate, one of the precursors of folate.

Q6- What are the functions of Carbamoyl synthetase (CPS)- I & II Answer: CPS-I is an enzyme located in the mitochondria involved in the production of . CPS-I transfers an molecule from glutamine or glutamate to a molecule of that has been phosphorylated by a molecule of ATP. It can only be activated by N-acetylglutamate. CPS-II is an enzyme that catalyzes the reactions that produce in the cytosol (as opposed to type I, which functions in the mitochondria) and it involve in pyrimidine synthesis. It is activated by ATP and PRPP and it is inhibited by UMP.

Q7- Give the reaction of purine biosynthesis via the salvage pathway Adenine, , guanine produced during the breakdown of high energy compounds like RNA and DNA, are salvaged to produce AMP, IMP, GMP. Adenine phosphoribosyl transferase catalyzes the formation of AMP from adenine.

Hypoxanthine-guanine phosphoribosyl transferase (HGPRT) catalyzes the formation of IMP and GMP from hypoxanthine and guanine respectively.

BCH 304 STUDY QUESTIONS & ANSWERS Biochemist Oh!Best

Phosphoribosyl pyrophosphate (PRPP) is the donor of ribose 5-phosphate in the salvage pathway.

Q8- Briefly explain the of Lesch-Nyhan’s syndrome Lesch Nyhan syndrome is an inherited X-linked recessive disorder that affects only males mostly. It is caused by a complete deficiency of HGPRTase [an enzyme involves in purine salvage pathway] and purine (hypoxanthine and guanine) will accumulate. The HGPRTase enzyme catalyzes the following two interconversions:

hypoxanthine + PRPP ↔ IMP + PPi

guanine + PRPP ↔ GMP + PPi The symptoms are: urinary tract stones, mental retardation or neurological symptoms, self-mutilation (biting of fingers), excessive production. It can be treated as follows; i. Use of : - It will only reduce uric acid formation, but does not alleviate the neurologic symptoms ii. Alkalanization of urine should be avoided. iii. High fluid intake.

Q9- Name one nucleotide that acts in each of the following: (a) Second messenger (b) Phosphoryl-group transfer (c) Activation of carbohydrates (d) Activation of acetyl groups (e) Transfer of electrons (f) DNA sequencing (g) (h) Allosteric effector Answer: (a) cAMP (b) ATP (c) UDP-glucose (d) acetyl CoA (e) NAD+, FAD (f) dideoxynucleotides (g) fluorouracil; (h) CTP inhibits ATCase.

BCH 304 STUDY QUESTIONS & ANSWERS Biochemist Oh!Best

Q10a- Discuss the De-novo synthesis of UMP UMP which is pyrimidine nucleotide is formed via the De-novo biosynthesis

DHO dehydrogenase + CO2

Carbamoyl phosphate Synthetase II [CPS-II]

Orotate

Orotate Phosphoribosyl transferase Carbamoyl phosphate [CAP]

Aspartate transcarbamylase [ATCase]

Orotidine-5-monophosphate [OMP]

Carbamoyl aspartate [CAA] OMP decarboxylase

Dihydroorotate [DHO] -5-monophosphate [UMP]

Q10b- How is this pathway regulated? The first two ; carbamoyl phosphate synthetase II [CPS-II] and aspartate transcarbamoylase [ATCase] are allosteric enzymes and are regulated allosterically.

Q11- If man did not lose his urate , gout would have been an unknown disease. Discuss? Gout is a clinical disorder caused by deposition of urate crystals in a joint leading to acute inflammatory response with acute pain. Most cases of gout present with the sudden onset of severe acute arthritis in a peripheral joint in the leg. Urate oxidase is a peroxisomal liver enzyme that catalyzes the enzymatic oxidation of uric acid into the more water-soluble . Urate oxidase is an endogenous enzyme found in most but not in humans, which was actually caused by two (2) independent nonsense or frameshift mutations. BCH 304 STUDY QUESTIONS & ANSWERS Biochemist Oh!Best

Allopurinol blocks the conversion of to uric acid, while the urate oxidase catalyzes the oxidation of uric acid to allantoin, a highly water-soluble metabolite readily excreted by the kidney. Although urate oxidase is not found in humans, but urate oxidase is used in humans for the control of increased serum uric acid in patients with acute tumour lysis syndrome after receiving chemotherapy.

Q12a-Highlight the reactions of purine nucleotide cycle The purine nucleotide cycle is a in which ammonia and fumarate are generated from aspartate and inosine monophosphate (IMP) in order to regulate the levels of adenine nucleotides. The cycle is composed of three enzyme-catalyzed reactions. The first stage is the deamination of the purine nucleotide (AMP) to form inosine monophosphate (IMP), catalyzed by the enzyme AMP deaminase: + AMP + H2O → IMP + NH4 The second stage is the formation of from IMP and the aspartate, which is coupled to the energetically favourable hydrolysis of GTP, and catalysed by the enzyme adenylosuccinate synthetase:

Aspartate + IMP + GTP → Adenylosuccinate + GDP + Pi Finally, Adenylosuccinate is cleaved by the enzyme adenylosuccinate to release fumarate and regenerate the starting material of AMP: Adenylosuccinate → AMP + Fumarate

Q12b- How is the above pathway relevant to muscle contraction? + This cycle has the net effect of converting aspartate to fumarate plus NH4 . It plays an important role in energy in skeletal muscle, where the fumarate that it generates replenishes the levels of citric acid cycle intermediates lost in amphibolic side reactions. Skeletal muscle lacks the usual complement of anaplerotic enzymes and relies on enhanced levels of AMP deaminase, adenylosuccinate synthetase, and to compensate. ATP → ADP + Pi (utilization of ATP for Muscle contraction) Purine nucleotide cycle occurs during strenuous exercise, fasting or starvation when ATP reservoirs run low.

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