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FCH 532 Lecture 28. Chapter 28: Nucleotide metabolism Quiz on Monday essential amino acids Wed. April 11-Exam 3 ACS exam is on Monday 5/30 Final is scheduled for May 4, 12:45-2:45 PM, in 111 Marshall.

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Fch 532 lecture 28
FCH 532 Lecture 28

Chapter 28: Nucleotide metabolism

Quiz on Monday essential amino acids

Wed. April 11-Exam 3

ACS exam is on Monday 5/30

Final is scheduled for May 4, 12:45-2:45 PM, in 111 Marshall


Figure 26-60 The biosynthesis of the “aspartate family” of amino acids: lysine, methionine, and threonine.

Page 1039


Figure 26 61 the biosynthesis of the pyruvate family of amino acids isoleucine leucine and valine
Figure 26-61 The biosynthesis of the “pyruvate family” of amino acids: isoleucine, leucine, and valine.

Page 1040


Figure 26 62 the biosynthesis of chorismate the aromatic amino acid precursor
Figure 26-62 The biosynthesis of chorismate, the aromatic amino acid precursor.

Page 1042


Figure 26 63 the biosynthesis of phenylalanine tryptophan and tyrosine from chorismate
Figure 26-63 The biosynthesis of phenylalanine, tryptophan, and tyrosine from chorismate.

Page 1043


Figure 26 64 a ribbon diagram of the bifunctional enzyme tryptophan synthase from s typhimurium
Figure 26-64 A ribbon diagram of the bifunctional enzyme tryptophan synthase from S. typhimurium

Page 1044


Figure 26 65 the biosynthesis of histidine
Figure 26-65 The biosynthesis of histidine.

Page 1045



Purine synthesis
Purine synthesis

  • Purine components are derived from various sources.

  • First step to making purines is the synthesis of inosine monophosphate.


De novo biosynthesis of purines: low molecular weight precursors of the purine ring atoms


Initial derivative is inosine monophosphate imp
Initial derivative is Inosine monophosphate (IMP) precursors of the purine ring atoms

  • AMP and GMP are synthesized from IMP

H

Hypoxanthine

base

O

-O

P

O-

Inosine monophosphate


Inosine monophosphate imp synthesis
Inosine monophosphate (IMP) synthesis precursors of the purine ring atoms

  • Pathway has 11 reactions.

  • Enzyme 1: ribose phosphate pyrophosphokinase

  • Activates ribose-5-phosphate (R5P; product of pentose phosphate pathway) to 5-phosphoriobysl--pyrophosphate (PRPP)

  • PRPP is a precursor for Trp, His, and pyrimidines

  • Ribose phosphate pyrophosphokinase regualtion: activated by PPi and 2,3-bisphosphoglycerate, inhibited by ADP and GDP.


Page 1071 precursors of the purine ring atoms


Activation of ribose-5-phosphate to PRPP precursors of the purine ring atoms

N9 of purine added

Page 1071


Anthranilate synthase precursors of the purine ring atoms

Anthranilate phosphoribosyltransferase

N-(5’-phosphoribosyl) anthranilate isomerase

Indole-3-glycerol phosphate synthase

Tryptophan synthase

Tryptohan synthase,  subunit

Chorsmate mutase

Prephenate dehydrogenase

Aminotransferase

Prephenate dehydratase

aminotransferase

Page 1043


ATP phosphoribosyltransferase precursors of the purine ring atoms

Pyrophosphohydrolase

Phosphoribosyl-AMP cyclohydrolase

Phosphoribosylformimino-5-aminoimidazole carboxamide ribonucleotide isomerase

Imidazole glycerol phosphate synthase

Imidazole glycerol phosphate dehydratase

L-histidinol phosphate aminotransferase

Histidinol phosphate phosphatase

Histidinol dehydrogenase

Page 1045


Page 1074 precursors of the purine ring atoms


Nucleoside diphosphates are synthesized by phosphorylation of nucleoside monophosphates
Nucleoside diphosphates are synthesized by phosphorylation of nucleoside monophosphates

Nucleoside diphosphates

  • Reactions catalyzed by nucleoside monophosphate kinases

Adenylate kinase

2ADP

AMP + ATP

Guanine specific kinase

GDP + ADP

GMP + ATP

  • Nucleoside monophosphate kinases do not discriminate between ribose and deoxyribose in the substrate (dATP or ATP, for example)


Nucleoside triphosphates are synthesized by phosphorylation of nucleoside monophosphates
Nucleoside triphosphates are synthesized by phosphorylation of nucleoside monophosphates

Nucleoside diphosphates

  • Reactions catalyzed by nucleoside diphosphate kinases

Adenylate kinase

ADP + GTP

ATP + GDP

  • Can use any NTP or dNTP or NDP or dNDP


Regulation of purine biosynthesis
Regulation of purine biosynthesis of nucleoside monophosphates

  • Pathways synthesizing IMP, ATP and GTP are individually regulated in most cells.

  • Control total purines and also relative amounts of ATP and GTP.

  • IMP pathway regulated at 1st 2 reactions (PRPP and 5-phosphoribosylamine)

  • Ribose phosphate pyrophosphokinse- is inhibited by ADP and GDP

  • Amidophosphoribosyltransferase (1st committed step in the formation of IMP; reaction 2) is subject to feedback inhibition (ATP, ADP, AMP at one site and GTP, GDP, GMP at the other).

  • Amidophosphoribosyltransferase is allosterically activated by PRPP.


Activation of ribose-5-phosphate to PRPP of nucleoside monophosphates

N9 of purine added

Page 1071


Figure 28 5 control network for the purine biosynthesis pathway
Figure 28-5 of nucleoside monophosphates Control network for the purine biosynthesis pathway.

Feedback inhibition is indicated by red arrows

Feedforward activation by green arrows.

Page 1075


Salvage of purines
Salvage of purines of nucleoside monophosphates

  • Free purines (adenine, guanine, and hypoxanthine) can be reconverted to their corresponding nucleotides through salvage pathways.

  • In mammals purines are salvaged by 2 enzymes

  • Adeninephosphoribosyltransferase (APRT)

    Adenine + PRPP  AMP + PPi

  • Hypoxanthine-guanine phosphoribosyltransferase (HGPRT)

    Hypoxanthine + PRPP  IMP + PPi

    Guanine + PRPP  GMP + PPi


Synthesis of pyrimidines
Synthesis of pyrimidines of nucleoside monophosphates

  • Pyrimidines are simpler to synthesize than purines.

  • N1, C4, C5, C6 are from Asp.

  • C2 from bicarbonate

  • N3 from Gln

  • Synthesis of uracil monoposphate (UMP) is the first step for producing pyrimidines.


Figure 28 6 the biosynthetic origins of pyrimidine ring atoms
Figure 28-6 of nucleoside monophosphates The biosynthetic origins of pyrimidine ring atoms.

Page 1077


Page 1077 of nucleoside monophosphates


Reaction 4 oxidation of dihydroorate reactions catalyzed by eukaryotic dihydroorotate dehydrogenase
Reaction 4: Oxidation of dihydroorate of nucleoside monophosphates Reactions catalyzed by eukaryotic dihydroorotate dehydrogenase.

Page 1078


Oxidation of dihydroorotate
Oxidation of dihydroorotate of nucleoside monophosphates

  • Irreversible oxidation of dihydroorotate to orotate by dihydroroorotate dehydrogenase (DHODH) in eukaryotes.

  • In eukaryotes-FMN co-factor, located on inner mitochondrial membrane. Other enzymes for pyrimidine synthesis in cytosol.

  • Bacterial dihydroorotate dehydrogenases use NAD linked flavoproteins (FMN, FAD, [2Fe-2S] clusters) and perform the reverse reaction (orotate to dihydroorotate)


Figure 28 9 reaction 6 proposed catalytic mechanism for omp decarboxylase
Figure 28-9 of nucleoside monophosphates Reaction 6: Proposed catalytic mechanism for OMP decarboxylase.

Decarboxylation to form UMP involves OMP decarboxylase (ODCase) to form UMP.

Enhances kcat/KM of decarboxylation by 2 X 1023

No cofactors

Page 1079


Synthesis of utp and ctp
Synthesis of UTP and CTP of nucleoside monophosphates

  • Synthesis of pyrimidine nucleotide triphosphates is similar to purine nucleotide triphosphates.

  • 2 sequential enzymatic reactions catalyzed by nucleoside monophosphate kinase and nucleoside diphosphate kinase respectively:

    UMP + ATP  UDP + ADP

    UDP + ATP  UTP + ADP


Figure 28 10 synthesis of ctp from utp
Figure 28-10 of nucleoside monophosphates Synthesis of CTP from UTP.

Page 1080

CTP is formed by amination of UTP by CTP synthetase

In animals, amino group from Gln

In bacteria, amino group from ammonia


Regulation of pyrimidine nucleotide synthesis
Regulation of pyrimidine nucleotide synthesis of nucleoside monophosphates

  • Bacteria regulated at Reaction 2 (ATCase)

  • Allosteric activation by ATP

  • Inhibition by CTP (in E. coli) or UTP (in other bacteria).

  • In animals pyrimidine biosynthesis is controled by carbamoyl phosphate synthetase II

  • Inhibited by UDP and UTP

  • Activated by ATP and PRPP

  • Mammals have a second control at OMP decarboxylase (competitively inhibited by UMP and CMP)

  • PRPP also affects rate of OMP production, so, ADP and GDP will inhibit PRPP production.


Page 1080 of nucleoside monophosphates


Production of deoxyribose derivatives
Production of deoxyribose derivatives of nucleoside monophosphates

  • Derived from corresponding ribonucleotides by reduction of the C2’ position.

  • Catalyzed by ribonucleotide reductases (RNRs)

dADP

ADP


Overview of dNTP biosynthesis of nucleoside monophosphates

One enzyme, ribonucleotide reductase,

reduces all four ribonucleotides to their

deoxyribose derivatives.

A free radical mechanism is involved

in the ribonucleotide reductase

reaction.

There are three classes of ribonucleotide

reductase enzymes in nature:

Class I: tyrosine radical, uses NDP

Class II: adenosylcobalamin. uses NTPs

(cyanobacteria, some bacteria,

Euglena).

Class III: SAM and Fe-S to generate

radical, uses NTPs.

(anaerobes and fac. anaerobes).


Figure 28-12a of nucleoside monophosphates Class I ribonucleotide reductase from E. coli. (a) A schematic diagram of its quaternary structure.

Page 1082


Proposed mechanism for rNDP reductase of nucleoside monophosphates


Proposed reaction mechanism for ribonucleotide reductase of nucleoside monophosphates

Free radical abstracts H from C3’

Acid-catalyzed cleavage of the C2’-OH bond

Radical mediates stabilizationof the C2’ cation (unshared electron pair)

Radical-cation intermediate is reduced by redox-active sulhydryl pair-deoxynucleotide radical

3’ radical reabstracts the H atom from the protein to restore the enzyme to the radical state.


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