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Chapter 10. Nucleotide metabolism. Function of neucleotides. Precursors for RNA and DNA synthesis Energy substance in body (ATP) Physiological Mediators (cAMP) Components of coenzymes (NAD + ) Allosteric effectors and donor of phosphate group ( phosphorylation )
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Chapter 10 Nucleotide metabolism
Function of neucleotides • Precursors for RNA and DNA synthesis • Energy substance in body (ATP) • Physiological Mediators (cAMP) • Components of coenzymes (NAD+) • Allosteric effectors and donor of phosphate group (phosphorylation) • Formation of activated intermediates UDP-glucose, CDP-choline
Section 10.2 Nucleotide Synthesis and Degradation
Nucleoprotein Protein Nucleic acid Nucleases Nucleotide Nucleotidase Absorption Phosphate Nucleoside Nucleosidase Base Ribose Digestion and absorption of nucleotide Blood
Metabolism of Purine nucleotides • Biosynthesis of purine nucleotides de novo synthesis 从头合成 salvage pathway 补救合成 AMP GMP
CO2 Glycine Aspartate One carbon unit One carbon unit Glutamine 1.De novo synthesis of purine nucleotides
Characteristics of de novo synthesis of purine nucleotides 1. in cytosol 2. form IMP first, then synthesize AMP and GMP from IMP. 3. formation of purines is based on the ribosyl group of 5’-phosphoribose
AMP ATP PRPPK Gln Glutamine PRPP amidotransferase (GPRT) Glu AMP GMP PP-1-R-5-P( 5’-phosphoribose 1’-pyrophosphate, PRPP) R-5-P (5’-phosphoribose) H2N-1-R-5´-P (5´-phosphoribosyl-amine) Gly, one carbon units, Gln, CO2, Asp involved step by step 磷酸核糖焦磷酸 IMP
_ _ _ + + R-5-P PRPPK GPAT IMP _ ATP GMP GTP XMP GDP _ Adenyl-succinate ADP ATP AMP _ + + _ Regulation of de novo synthesis of purine nucleotides PRPP PRA Adenyl-succinate GTP ATP AMP ADP IMP XMP GTP GMP GDP ATP
2. Salvage synthesis of purine nucleotides • Material: PRPP, purine (conjunction) nucleosides (phosphorylation) • Location: brain and bone marrow or
APRT adenine+PRPP AMP + PPi HGPRT hypoxanthine+PRPP IMP + PPi HGPRT guanine+PRPP GMP + PPi Adenylate kinase adenosine AMP ATP ADP APRT: adenine phosphoribosyltransferase HGPRT: hypoxanthine-guanine phosphoribosyltransferase
Degradation of purine nucleotides nucleotide nucleosides ribose-1-phosphate purine salvage pathway uric acid Nucleotidase Nucleoside phosphorylase 尿酸
IMP Neucleo-tidase Excretion
Metabolism of pyrimidine nucleotides • Biosynthesis of pyrimidine nucleotides de novo synthesis salvage pathway
1.De novo synthesis of pyrimidine nucleotides 4 Glutamine 3 5 Aspartate CO2 2 6 1
Characteristics of de novo synthesis of pyrimidine nucleotides 1. mostly in cytosol 2. form UMP first, then synthesize other pyrimidine nucleotides from UMP. 3. in the synthesis of UMP, pyrimidine ring is formed first , then combined with PRPP.
Process of de novo synthesis of UMP • 1. formation of Carbamoyl phsphate (CP) CO2 + glutamine + H2O + 2ATP Carbamoyl phosphate synthaseⅡ (CPSⅡ) O O~PO32- + 2ADP + Pi H2N C carbamoyl phosphate
The different between Carbamoyl phosphate synthaseⅠ,Ⅱ Mitochondria of liver cells cytosol of all cells Location Source of nitrogen NH3 Glutamine N-acetylglutamate None Activator Formation of pyrimidine Function Formation of urea
O O~PO32- H2N C carbamoyl phosphate 2. Formation of UMP + Aspartate Carbamoyl aspartate Orotate乳清酸 PRPP UMP
CTP synthase UMPK NDK ATP ADP Gln ATP ATP ADP Glu ADP dUDP dCMP dTMP dUMP TMP synthase 3. Synthesis of CTP, dTMP or TMP UDP UTP
+ - - Purine nucleotides + - Pyrimidine nucleotides Regulation of de novo synthesis of pyrimidine nucleotides ATP + CO2+ glutamine • Activated by substrates • Inhibited by products Carbamoyl phosphate - aspartate Carbamoyl aspartate ATP + 5-phosphate ribose PRPP UMP UTP CTP -
Uracil phosphate ribosyltransferase Uracil +PRPP UMP+ PPi Uridine kinase Uridine+ ATP UMP +ADP Uridine phosphorylase Uracil+ 1-phosphoribose Uridine + Pi Salvage pathway of pyrimidine nucleotides
Degradation of pyrimidine nucleotides nucleotide nucleosides phosphoribose pyrimidine Nucleotidase Nucleoside phosphorylase
Thymine β-ureidoisobutyrate H2O β-aminoisobutyrate Excreted in urine Succinyl CoA Glucose TAC Cytosine NH3 Uracil dihydrouracil H2O + + CO2 + NH3 β-alanine liver Acetyl CoA Urea TAC
dNDP NDP Deoxyribonucleotide biosynthesis Ribonucleotide reductase kinase dNDP+ATP dNTP + ADP
Kinase Kinase ATP ADP ATP ADP Kinase Kinase XMP XDP XTP YTP YDP YTP YDP Biosynthesis of NDP and NTP AMP ADP ATP
Section 10.3 Dysmetabolism of nucleotides and antimetabolites
Dysmetabolism of nucleotides • Caused by the genetic defect or regulatory abnormality of some enzymes participating nucleotide metabolism. Gout(痛风):pain and tenderness, redness, heat, swelling and joint inflammation Causes:too much uric acid forms crystals in joints and cause inflammation
Risk Factors • Obesity/being overweight • more common in men than women • Certain medicines • Certain foods and alcoholic beverages • Genetics • Enzyme defect
Medication • xanthine-oxidase inhibitors, 黄嘌呤氧化酶抑制剂 allopurinol别嘌呤醇 • uricosurics, 促尿酸尿剂 • urate oxidases尿酸氧化酶
Limit your consumption of certain types of meat:beef, pork, lamb, and “organ meats” (such as liver, kidney, and brain), as well as meat extracts and gravies. • Reduce or eliminate alcohol consumption, especially beer. • Reduce your use of oatmeal, dried beans, spinach, asparagus, cauliflower, and mushrooms • High consumption of seafood is associated with an increased risk of gout.
Antimetabolites • The analogs of ribonucleotide metabolite intermediates synthesized artificially. • Can interfere, inhibit and block the ribonucleotide metabolism. • Used as drugs.
Purine ribonucleotide metabolite analogs 6-mercaptopurine(6-MP) Hypoxanthine (6-MP)
Pyrimidine ribonucleotide metabolite analogs : 5-fluorouracil(5-FU), (T) (5-FU)
NAD+ AMP
Biological oxidation • Respiratory Chain and its composition ,How many Respiratory Chain in the mitochondria? What is the sequence of them? • Oxidation Phosphorylation and the mechanism of it • the regulation of it (Cyanide)? • P/O ratio • How many ATP produced by Respiratory Chain? How to use cytosolic NADH ? • energy-rich compounts
Protein catabolism • Nitrogen Balance, Essential Amino Acids , Complementary effect, Putrefaction, Amino acid metabolic pool, Ketogenic amino acids, Ketogenic and glucogenic amino acids. • deamination, decarboxylation key enzymes, main pathway, main products
ALT, AST(function) • SAM, PAPS, GSH, Dopamine , creatine phosphate (function, formation) • Ammonia, One Carbon Units carrier, source, utilization • Hyperammonemia, PKU, Albinism damage, mechanism
Nucleotide metabolism • Function of neucleotides • de novo synthesis of purine and pyrimidine nucleotides material, character, main steps, • Salvage pathwayof purine and pyrimidine • Degradationof purine and pyrimidine nucleotides products ,Gout • Deoxyribonucleotide biosynthesis