Nucleic Acid Metabolism Nucleotides Essential for all cells

Nucleic Acid Metabolism • Nucleotides – – Essential for all cells DNA RNA Carriers of activated intermediates in carbohydrate, lipids and proteins • • Co. A FAD NADP – Energy Carriers • ATP – Inhibiting or activating enzymes

de novo ﻣﺴیﺮ ﺳﻨﺘﺰ ﺍﺯ ﻧﻮ یﺎ پﻮﺭیﻦ ﻫﺎ Isotopic labeling experiments defined the precursors.

Synthesis of purine nucleotides C Y T O P L A S M

: ﺗﺸکیﻞ ﻓﺴﻔﻮﺭیﺒﻮﺯیﻞ پیﺮﻭﻓﺴﻔﺎﺕ ATP Ribose 5 -phosphate PRPP synthase ADP PRPP: 5 -Phosphoribose-1 -pyrophosphate

ﻣﺮﺣﻠﻪ کﻨﺘﺮﻝ کﻨﻨﺪﻩ ﻣﺴیﺮ ﺳﻨﺘﺰ Glutamine glutamate + PPi Gln PRPP Amidotransferase PRPP 5 -phosphoribosyl-1 -amine

IMP GMP AMP

5) Formation of ATP and GTP AMP Kinase ATP GMP ADP Kinase ATP ADP GDP Phosphorylation Pi Kinase ATP ADP ATP GTP

: ﻣﺴیﺮ ﺑﺎﺯیﺎﺑی پﻮﺭیﻦ ﻫﺎ Salvage Pathways Specific Enzymes Adenosine phosphoribosyltransferase(APRT) Hypoxanthine-guanine phosphotransferase (HGPRT)

Synthesis of pyrimidine nucleotides C Y T O P L A S M mitochondrion Dihydro orotate dehydrogenase (the only mitochondrial enzyme)

Formation of carbamoyl phosphate Gln Glu 2 ATP + HCO 3 Carbamoyl phosphate synthase-II + 2 ADP+ Pi

ﺗﻔﺎﻭﺕ ﺑیﻦ ﺗﻮﻟیﺪ کﺎﺭﺑﺎﻣیﻞ ﻓﺴﻔﺎﺕ ﺩﺭ ﺳیکﻞ ﺍﻭﺭﻩ ﻭ ﺩﺭ ﺑیﻮﺳﻨﺘﺰ پیﺮیﻤیﺪیﻦ ﻫﺎ Location -NH 2 from: Enzyme N-acetyl-Glu In pyrimidine pathway Cytosol Gln Carbamoyl phosphate synthase-II No effect In urea cycle Mitochondria NH 4+ Carbamoyl phosphate synthase-I Activator

Regulation of nucleotide synthesis regulatory enzyme activation glutamine-PRPP amidotransferase (purines) PRPP carbamoylphosphate synthetase II PRPP ATP (pyrimidines) = cytosolic inhibition IMP, GMP, AMP (allosteric inhibition) UTP

ﻧﻮکﻠﺌﻮﺗیﺪﻫﺎی Salvage ﻣﺴیﺮ ﺑﺎﺯیﺎﺑی پیﺮیﻤیﺪیﻨی PRPP Pyrimidine Phosphoribosyl transferase PRPP Orotate PPi Orotate Phosphoribosyl transferase Pyrimidine ribonucleoside monophosphate H+ CO 2 Orotidylate decarboxylase UMP

: ﺑیﻮﺳﻨﺘﺰ ﺩﺯﻭکﺴی ﻧﻮکﻠﺌﻮﺗیﺪﻫﺎ Base=purine or pyrimidine Ribonucleoside diphosphate deoxyribonucleoside diphosphate

ﺗیﻤیﺪیﻼﺕ ﺳﻨﺘﺎﺯ Thymidylate synthase inhibitor : Examples include Raltitrexed, used for colorectal cancer since 1998 Fluorouracil, used for colorectal cancer

ﺗﺨﺮیﺐ ﻧﻮکﻠﺌﻮﺗیﺪﻫﺎی پﻮﺭیﻨی q AMP IMP GMP Hypoxanthine Guanine Xanthine Uric acid

Purine Catabolism uric acid 1. Remove phosphate. -5’-nucleotidase 1 a. Deaminate adenosine -Adenosine deaminase 2. Remove the ribose. -nucleosidase 3. Generate xanthine. -oxidize hypoxanthine -deaminate guanine 4. Make uric acid. -xanthine oxidase

Degradation of pyrimidines

ﻣﺤﺼﻮﻻﺕ ﺗﺨﺮیﺐ ﻧﻮکﻠﺌﻮﺗیﺪﻫﺎی پیﺮیﻤیﺪیﻨی ü The pyrimidine ring can be completely degraded in humans. ü The products include: NH 3, CO 2, -alanine, and -aminoisobutyrate. ü Both b-alanine, and b-aminoisobutyrate can be further converted into acetyl-Co. A and succinyl-Co. A, respectively, or are excreted in the urine.

Principal differences between metabolism of purines and pyrimidines purines formation of N-glycosidic bond in 1 st step of their biosynthesis (PRPP is the 1 st substrate) pyrimidines a heterocyclic ring is formed first, then it reacts with PRPP location of biosynthesis cytoplasm + 1 enzyme is in a mitochondrion Dihydro orotate dehydrogenase products of degradation uric acid CO 2, NH 3, -AMK, -alanine (poor solubility in H 2 O), NH 3 (soluble in H 2 O)

: ﻧﻮکﻠﺌﻮﺗیﺪﻫﺎی ﺣﻠﻘﻮی These include: • cyclic AMP • cyclic GMP • cyclic ADP-ribose • These function as second messengers associated with G proteins and calcium signaling.

Coenzyme A Pathway Uses • Pantothenate • ATP, CTP, • Cysteine

FMN and FAD • Riboflavin and Consumes ATP