FCH 532 Lecture 10 Extra credit posted on website, due on Friday (email or typed copy) Chapter 29.
FCH 532 Lecture 29 Chapter 28: Nucleotide metabolism Chapter 24: Photosynthesis New study guide...
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Transcript of FCH 532 Lecture 29 Chapter 28: Nucleotide metabolism Chapter 24: Photosynthesis New study guide...
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FCH 532 Lecture 29
Chapter 28: Nucleotide metabolismChapter 24: PhotosynthesisNew study guide posted
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Figure 26-1cd Forms of pyridoxal-5-phosphate.(c) Pyridoxamine-5-phosphate (PMP) and (d) The Schiff base that forms between PLP and an enzyme -amino
group.
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Figure 26-13The serine dehydratase reaction.P
age
997
1. Formation of Ser-PLP Schiff base, 2. Removal of the -H atom of serine, 3. elimination of OH-, 4. Hydrolysis of Schiff base, 5. Nonenzymatic tautomerization to the imine, 6. Nonenzymatic hydrolysis to form pyruvate and ammonia.
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Serine hydroxymethyltransferase catalyzes PLP-dependent C-C
cleavage
• Catalyzes the conversion of Thr to Gly and acetaldehyde
• Cleaves C-C bond by delocalizing electrons of the resulting carbanion into the conjugated PLP ring:
+N
H
CH3
2-O3PO
CN
HH
O-
H3C-HC--C-COO-
O H
HB:
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Figure 26-54The syntheses of alanine, aspartate, glutamate,
asparagine, and glutamine.
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Figure 26-58The conversion of glycolytic intermediate 3-
phosphoglycerate to serine.
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1. Conversion of 3-phosphoglycerate’s 2-OH group to a ketone
2. Transamination of 3-phosphohydroxypyruvate to 3-phosphoserine
3. Hydrolysis of phosphoserine to make Ser.
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Purine synthesis
• Purine components are derived from various sources.• First step to making purines is the synthesis of inosine
monophosphate.
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De novo biosynthesis of purines: low molecular weight precursors of the purine
ring atoms
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Initial derivative is Inosine monophosphate (IMP)
• AMP and GMP are synthesized from IMP
H
P
O-
-O
O Hypoxanthinebase
Inosine monophosphate
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Inosine monophosphate (IMP) synthesis
• 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.
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1. Activation of ribose-5-phosphate to PRPP
2. N9 of purine added
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1. Anthranilate synthase
2. Anthranilate phosphoribosyltransferase
3. N-(5’-phosphoribosyl) anthranilate isomerase
4. Indole-3-glycerol phosphate synthase
5. Tryptophan synthase
6. Tryptohan synthase, subunit
7. Chorsmate mutase
8. Prephenate dehydrogenase
9. Aminotransferase
10. Prephenate dehydratase
11. aminotransferase
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1. ATP phosphoribosyltransferase
2. Pyrophosphohydrolase
3. Phosphoribosyl-AMP cyclohydrolase
4. Phosphoribosylformimino-5-aminoimidazole carboxamide ribonucleotide isomerase
5. Imidazole glycerol phosphate synthase
6. Imidazole glycerol phosphate dehydratase
7. L-histidinol phosphate aminotransferase
8. Histidinol phosphate phosphatase
9. Histidinol dehydrogenase
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Nucleoside diphosphates are synthesized by phosphorylation of nucleoside
monophosphates Nucleoside diphosphates• Reactions catalyzed by nucleoside monophosphate kinases
AMP + ATP 2ADPAdenylate kinase
GMP + ATP GDP + ADPGuanine specific kinase
• Nucleoside monophosphate kinases do not discriminate between ribose and deoxyribose in the substrate (dATP or ATP, for example)
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Nucleoside triphosphates are synthesized by phosphorylation of nucleoside monophosphates
Nucleoside diphosphates• Reactions catalyzed by nucleoside diphosphate kinases
ATP + GDP ADP + GTPAdenylate kinase
• Can use any NTP or dNTP or NDP or dNDP
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Regulation of purine biosynthesis
• 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.
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1. Activation of ribose-5-phosphate to PRPP
2. N9 of purine added
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Figure 28-5Control network for
the purine biosynthesis
pathway.
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Feedback inhibition is indicated by red arrows
Feedforward activation by green arrows.
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Salvage of purines
• 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
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Synthesis of pyrimidines
• 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.
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Figure 28-6 The biosynthetic origins of pyrimidine ring atoms.
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Reaction 4: Oxidation of dihydroorateReactions catalyzed by eukaryotic dihydroorotate
dehydrogenase.
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Oxidation of dihydroorotate
• 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)
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Figure 28-9 Reaction 6: Proposed catalytic mechanism for OMP decarboxylase.
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Decarboxylation to form UMP involves OMP decarboxylase (ODCase) to form UMP.
Enhances kcat/KM of decarboxylation by 2 X 1023
No cofactors
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Synthesis of UTP and CTP• 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
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Figure 28-10 Synthesis of CTP from UTP.
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CTP is formed by amination of UTP by CTP synthetase
In animals, amino group from Gln
In bacteria, amino group from ammonia
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Regulation of pyrimidine nucleotide synthesis
• 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.
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Production of deoxyribose derivatives
• Derived from corresponding ribonucleotides by reduction of the C2’ position.
• Catalyzed by ribonucleotide reductases (RNRs)
ADP dADP
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Overview of dNTP biosynthesis
One enzyme, ribonucleotide reductase,reduces all four ribonucleotides to theirdeoxyribose derivatives.
A free radical mechanism is involvedin the ribonucleotide reductasereaction.
There are three classes of ribonucleotidereductase enzymes in nature:Class I: tyrosine radical, uses NDPClass II: adenosylcobalamin. uses NTPs
(cyanobacteria, some bacteria,Euglena).
Class III: SAM and Fe-S to generateradical, uses NTPs.(anaerobes and fac. anaerobes).
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Figure 28-12a Class I ribonucleotide reductase from E. coli. (a) A schematic diagram of its
quaternary structure.
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Proposed mechanism for rNDP reductase
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Proposed reaction mechanism for ribonucleotide reductase
1. Free radical abstracts H from C3’
2. Acid-catalyzed cleavage of the C2’-OH bond
3. Radical mediates stabilizationof the C2’ cation (unshared electron pair)
4. Radical-cation intermediate is reduced by redox-active sulhydryl pair-deoxynucleotide radical
5. 3’ radical reabstracts the H atom from the protein to restore the enzyme to the radical state.
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Thioredoxin and glutaredoxin
• Final step in the RNR catalytic cycle is the reduction of disulfide bond to reform the redox-active sulfyhydryl pair).
• Thioredoxin-108 residue protein that has redox active Cys (Cys32 and Cys35)-also involved in the Calvin Cycle.
• Reduces oxidized RNR and is regenerated via NADPH by thioredoxin reductase.
• Glutaredoxin is an 85 residue protein that can also reduce RNR.• Oxidized glutaredoxin is reuced by NADPH using glutredeoxin
reductase.
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Sources of reducing power for rNDP reductase
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Proposed reaction mechanism for ribonucleotide reductase
1. Free radical abstracts H from C3’
2. Acid-catalyzed cleavage of the C2’-OH bond
3. Radical mediates stabilizationof the C2’ cation (unshared electron pair)
4. Radical-cation intermediate is reduced by redox-active sulhydryl pair-deoxynucleotide radical
5. 3’ radical reabstracts the H atom from the protein to restore the enzyme to the radical state.
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dNTPs made by phosphorylation of dNDP
• Reaction is catalyzed by nucleoside diphosphate kinase (same enzyme that phosphorylates NDPs)
dNDP + ATP dNTP + ADP
• Can use any NTP or dNTP as phosphoryl donor.
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Thymine synthesis
• 2 main enzymes: dUTP diphosphohydrolase (dUTPase) and thymidylate synthase
Reaction 1• dTMP is made by methylation of dUMP.• dUMP is made by hydrolysis of dUTP via dUTP diphosphohydrolase (dUTPase)
dUTP + H2O dUMP+ PPi
• Done to minimize the concentration of dUTP-prevents incorporation of uracil into DNA.
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Thymine synthesis Reaction 2• dTMP is made from dUMP by thymidylate synthase (TS).• Uses N5, N10-methylene-THF as methyl donor
+
+
dUMP
dTMP
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1. Enzyme Cys thiolate group attacks C6 of dUMP (nucleophile).
2. C5 of the enolate ion attacks the CH2 group of the imium cation of N5, N10-methylene-THF.
3. Enzyme base abstracts the acidic proton at C5, forms methylene group and eliminates THF cofactor
4. Migration of the N6-H atom of THF to the exocyclic methylene group to form a methyl group and displace the Cys thiolate intermediate.
Figure 28-19 Catalytic mechanism of thymidylate synthase.
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5-flurodeoxyuridylate (FdUMP)
• Antitumor agent.• Irreversible inhibitor of TS• Binds like dUMP but in
step 3 of the reaction, F cannot be extracted.
• Suicide substrate.
FdUMP
F
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Figure 28-20The X-ray structure of the E. coli thymidylate synthase–FdUMP–THF ternary complex.
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Thymine synthase oxidizes N5,N10-methyleneTHF
• Only enzyme to change the oxidation state of THF.• Regenerated by 2 reactions• DHF is reduced to THF by NADPH by dihydrofolate
reductase.• Serine hydroxymethyltransferase transfers the
hydroxymethyl group of serine to THF to regenerate N5,N10-methylene-THF and produces glycine.