1. Andy Howard Biochemistry Lectures, Spring 2019 Tuesday 30 April 2019
Nitrogen Metabolism 2
Andy Howard Biochemistry Lectures, Spring 2019 Tuesday 30 April 2019

2. Amino acid breakdown; Nucleoside Synthesis
Amino acid catabolism feeds the TCA cycle and acetyl CoA
Nucleosides and nucleotides are built up from PRPP, amino acids, and other building-blocks
Deoxyribonucleosides are derived from nucleosides via ribonucleotide reductase
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Nitrogen Metabolism 2

3. What we’ll discuss Amino acid catabolism Nucleoside biosynthesis
Ser, gly, his, val
other glucogenics
Leu & Lys
Nucleoside biosynthesis
Urea cycle
Pyrimidine biosynthesis
Purine biosynthesis
Ribonucleotide reductase
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4. What do we do with amino acids?
Obviously a lot of them serve as building-blocks for protein and peptide synthesis via ribosomal mechanisms
Also serve as metabolites, getting converted to other compounds (including nucleic acids) or getting oxidized as fuel
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5. Serine-based metabolites
Serine is a building block for sphinganine and therefore for sphingolipids
Serine also leads to phosphatidylserine, which is important by itself and can be metabolized to phosphatidylethanolamine and phosphatidylcholine
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6. Serine degradation Two paths for degrading serine:
PLP-dependent serine dehydratase simply deaminates ser to pyruvate; this enzyme is like trp synthase
More common: SHMT transfers hydroxymethyl group to tetrahydrofolate, leaving glycine; we’ve seen that one as a biosynthetic enzyme for making glycine
Human Serine dehydratase 41 kDa monomer EC PDB 1P5J, 2.5Å
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7. Glycine-based metabolites
porphobilinogen
Glycine is a source for purines, glyoxylate, creatine phosphate, and (with the help of succinyl CoA) porphobilinogen, whence we get porphyrins, and from those we get chlorophyll, heme, and cobalamin
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8. Glycine cleavage system
Glycine + H2O + NAD+ + THF  NADH + H+ + HCO3- + NH4+ + 5,10-methyleneTHF
Complex system: PLP, lipoamide, FAD prosthetic groups
Lipoamide swinging arm works as in pyruvate dehydrogenase
Pyrococcus T protein of glycine cleavage system EC kDa dimer PDB 1V5V, 1.5Å
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9. asp, glu, ala degradation I
Standard transmination converts aspartate to oxaloacetate with release of glutamate, which then can be deaminated to re-form -ketoglutarate:
aspartate + -ketoglutarate  oxaloacetate + glutamate
glutamate + NAD+ + H2O  -ketoglutarate + NADH + H+ + NH4+
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10. Asp, glu, ala degradation II
Deamination converts glutamate to -ketoglutarate, as above
Standard transamination converts alanine to pyruvate according to the same logic as asp
Pyrococcus GluDH EC kDa trimer PDB 1GTM, 2/2Å
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11. All three of these are glucogenic!
-ketoglutarate and oxaloacetate are TCA cycle intermediates
Pyruvate can be regarded as a glucose precursor via the gluconeogenesis pathways (pyr  OAA  PEP …)
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12. Degradation of asn, gln
Asparagine and glutamine are deaminated on side-chains to asp & glu
Thus they lead to oxaloacetate and - ketoglutarate, respectively
So they’re glucogenic
The initial deaminations are catalyzed by asparaginase and glutaminase
Erwinia chrysanthemi Asparaginase PDB 1O7J 144 kDa tetramer EC , 1Å
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13. Arginine degradation
Arginine is hydrolyzed to urea and ornithine as part of the urea cycle; enzyme is arginase
PLP-dependent enzyme converts ornithine to glu -semialdehyde
That’s oxidized to glutamate
Human arginase 212 kDa hexamer
Dimer shown
EC PDB 2AEB, 1.29Å
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14. Proline degradation
Thermus Proline dehydrogenase EC kDa dimer PDB 2EKG, 1.9Å
Proline oxidized back to 1-Pyrroline 5-carboxylate
O2 is oxidizing agent
different enzyme from forward reaction
Ring opened non-enzymatically to form glutamate -semialdehyde; see arginine
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15. urocanate
His degradation I
3 reactions from histidine to N-formiminoglutamate; first (histidine ammonia lyase) makes urocanate from histidine
Tetrahydrofolate-dependent reaction produces glutamate and 5-formiminoTHF
Pseudomonas HAL 224 kDa tetramer monomer shown EC PDB 1GKM, 1Å
N-formiminoglutamate
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16. His degradation II
5-formiminoTHF is enzymatically deaminated to 5,10-methyleneTHF, which can be used in purine synthesis, etc.
Rattus FTCD
EC kDa tetramer PDB 2PFD, 3.3Å
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17. How are we doing so far?
We did ser and gly first because they’re so important
Then we’ve done a whole bunch that connect up to glutamate (or asp): asp, glu, ala, asn, gln, arg, pro, his
So we’re halfway through.
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18. Threonine degradation
Several pathways:
Major one: oxidize threonine to 2-amino-3-ketobutyrate
2-amino-3-ketobutyrate reacts with HS-CoA; makes acetyl CoA & glycine
So this one is partly ketogenic
Other pathways are glucogenic
Pyrococcus
threonine dehydrogenase 116 kDa trimer
EC PDB 2DFV, 2.05Å
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19. Val degradation I Valine transaminated to -ketoisovalerate
Branched-chain -keto acid dehydrogenase (TPP, Lipoamide): -ketoisoavalerate + NAD+ + HS-CoA  -ketoisovaleryl CoA + NADH + H+
α-keto-isovalerate
PDB 2VBF 125 kDa dimer Lactococcus EC Å
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20. Val degradation II
Next reaction (acyl CoA dehydrogenase) -ketoisovaleryl CoA  2-methyl-1-propenyl CoA + NADH + CO2
Product undergoes 4 reactions to propionyl CoA and thence to succinyl CoA: glucogenic
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21. Isoleucine & leucine degradation
Same path but products are:
Leucine’s products: acetyl CoA + acetoacetate: ketogenic
Isoleucine: Acetyl CoA + propionyl CoA: ketogenic and glucogenic
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22. Methionine degradation I
Considerable methionine is turned into S-adenosylmethionine:
Methyl donor
Leaves behind S-Adenosylhomocysteine
S-adenosylhomocysteine can be hydrolyzed to homocysteine and adenosine
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23. Methionine degradation II
Homocysteine can condense with serine to form cystathionine, which can yield cysteine and -ketobutyrate… and we know how to turn -ketobutyrate into propionyl CoA. So met is glucogenic.
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24. Cysteine degradation
Most common: oxidation to cysteinesulfinate, which transaminates to form -sulfinylpyruvate: cysteine + O2  cysteinesulfinate + H+
-sulfinylpyruvate undergoes nonenzymatic desulfuration to SO2 and pyruvate. So cysteine is glucogenic.
Rat Cysteine dioxygenase 22 kDa monomer EC PDB 2B5H,1.5Å
Cysteine- sulfinate
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25. Phenylalanine
Tetrahydro-biopterin
Simple: phenylalanine gets hydroxylated to form tyrosine: phe + O2  tyrosine
This is a Fe2+ and tetrahydrobiopterin- dependent enzyme—a folate-like cofactor
Phenylalanine hydroxylase 71 kDa dimer; monomer shown human (residues ) EC PDB 1J8U, 1.5Å
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26. Phenylketonuria
Usually associated with mutation in phenylalanine hydroxylase:
Accumulated Phe  phenylpyruvate
Afflicts 1/15000 newborns
Built-up phenylpyruvate causes irreversible mental retardation
Type IV PKU related to deficiencies in enzymes that restore tetrahydrobiopterin
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27. Tyr degradation Transaminated and mutated to homogentisate
Three more reactions convert that to fumarate + acetoacetate
So tyr (and phe) are both ketogenic and glucogenic
Human Homogentisate dioxygenase 311 kDa hexamer
Monomer shown EC PDB 1EYB, 1.9 Å
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28. Trp degradation Tryptophan: need to open 2 rings!
8 reactions lead to alanine and - ketoadipate; first is trp + O2  N’-formylkynurenine
Alanine transaminated to pyruvate
-ketoadipate: 6 more reactions to 2 acetyl CoA + 2CO2
So it’s ketogenic and glucogenic
Human Indoleamine 2,3-dioxygenase EC kDa dimer monomer shown PDB 2D0T, 2.3Å
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29. Lys degradation
saccharopine
Condense lysine with -ketoglutarate to form saccharopine
That’s deglutamated (?), oxidized, transaminated to -ketoadipate
Six reactions to 2 acetyl CoA + 2 CO2
Purely ketogenic
Some bacteria decarboxylate it to cadaverine
Yeast Saccharopine dehydrogenase EC PDB 2AXQ, 1.7Å 103 kDa dimer monomer shown
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30. Urea cycle: overview ornithine
This is a significant pathway in the eukaryotic management of nitrogen- containing compounds
Among the first biochemical pathways to be carefully characterized—by Krebs and coworkers!
Proceeds via ornithine & citrulline to urea & (in some organisms) uric acid
urea
citrulline
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31. Making carbamoyl phosphate
Carboxy-phosphate
Making carbamoyl phosphate
Bicarbonate is phosphorylated to form carboxyphosphate
Ammonia condenses with that to form carbamate and Pi
Second ATP-phosphorylation forms carbamoyl phosphate
Carbamate
Carbamoyl phosphate
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32. Urea cycle itself
In mitochondrion: carbamoyl phosphate condenses with ornithine to form citrulline
In cytosol: Citrulline condenses with aspartate to form argininosuccinate
In cytosol: argininosuccinate is cleaved enzymatically to fumarate and arginine
In cytosol: arginine cleaved enzymatically to yield urea and ornithine
Ornithine to mitochondrial matrix, re-enters cycle
arginino-succinate
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33. Making citrulline
ornithine
carbamoyl phosphate condenses with ornithine to form citrulline via ornithine transcarbamoylase
Carbamoyl phosphate
E.coli OTCase EC kDa trimer PDB 1DUV, 1.7Å
citrulline
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34. First cytosolic step
Citrulline crosses mitochondrial membrane & fuses with aspartate to form argininosuccinate: Citrulline + aspartate + ATP  Argininosuccinate + AMP + PPi
Catalyzed by argininosuccinate synthetase
E.coli argininosuccinate synthetase EC kDa tetramer; monomer shown PDB 1K92, 1.6Å
Argininosuccinate
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35. arginine
2nd cytosolic step
fumarate
Argininosuccinate splits into fumarate and arginine via argininosuccinate lyase
Arginine gets used or else goes on to the third step
Duck δ2-crystallin EC kDa tetramer PDB 1K7W, 2Å
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36. L-ornithine
Final cytosolic step
urea
Arginine dehydrates to urea & ornithine via arginase
Ornithine passes into mitochondrion; cycle continues
Urea excreted or modified and excreted
Human arginase-1 EC kDa hexamer; dimer shown PDB 4HWW, 1.3Å
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37. Pyrimidine biosynthesis
Cytoplasmic, based on PRPP, bicarbonate, glutamine, aspartate
Intermediate is orotate (6-carboxyuracil) which gets attached to phosphoribose and then decarboxylated to make UMP
UMP UTP; gln + UTP  glu + CTP
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38. PRPP synthetase
Activation of ribose-5-P (see Calvin cycle, etc.) by ATP: -ribose-5-P + ATP  PRPP + AMP
Enzyme also called ribose-phosphate diphosphokinase
PRPP has roles in other systems too
Human PRPP synthetase 215 kDa hexamer; dimer shown EC PDB 2H06, 2.2Å
Phosphoribosyl pyrophosphate
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39. Pyrimidine synthesis: carbamoyl aspartate
Carbamoyl phosphate
Pyrimidine synthesis: carbamoyl aspartate
Uridine is based on orotate, derived from carbamoyl aspartate
We’ve already seen the carbamoyl phosphate synthesis a moment ago via carbamoyl phosphate synthetase
Carbamoyl phosphate + aspartate  carbamoyl aspartate + Pi via aspartate transcarbamoylase
Carbamoyl aspartate
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40. Aspartate transcarbamoylase
ATCase is the classic allosteric enzyme
E.coli version is inhibited by pyrimidine nucleotides and activated by ATP
CTP by itself is 50% inhibitory; CTP+ UTP is almost totally inhibitory
E.coli ATCase Trimer of heterotetramers 1 heterotetramer shown EC PDB 1D09, 2.1Å
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41. Carbamoyl aspartate to dihydroorotate
Carbamoyl aspartate dehydrates and cyclizes to L-dihydroorotate via dihydroorotase
TIM barrel protein
E.coli dihydroorotase EC
78 kDa dimer
PDB 2Z26, 1.3Å
Dihydro-orotate
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42. Dihydroorotate to orotate
Ubiquinone acts as oxidizing agent reducing the 5 & 6 Carbons via dihydroorotate dehydrogenase
Some versions incorporate FMN
Trypanosoma cruzi DHODH 69 kDa dimer EC PDB 2E6F, 1.3Å
orotate
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43. Adding phosphoribose Orotate + PRPP  orotidine 5’-monophosphate + PPi
Usual argument re pyrophosphate hydrolysis
Enzyme: orotidine phosphoribosyl transferase
Saccharomyces OPRTase 51kDa dimer E.C PDB 2PS1, 1.8Å
Orotidine 5’-monophosphate
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44. Decarboxylation OMP decarboxylated to form UMP via OMP decarboxylase
Bacterial forms are TIM barrel proteins
Acceleration is 1017-fold relative to uncatalyzed rate
Methanothermobacter OMP decarboxylase 28 kDa monomer EC PDB 3W07, 1.03Å
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45. Eukaryotic variation
Orotate produced in the mitochondrion moves to the cytosol
UMP synthase combines the last two reactions—orotidine to OMP to UMP
OMP decarboxylase domain of human UMP synthase 64 kDa dimer PDB 3MI2, 1.2Å
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46. UMP to UTP
Uridylate kinase converts UMP to UDP: UMP + ATP  UDP + ADP enzyme is related to several amino acid kinases
Nucleoside diphosphate kinase exchanges di for tri: UDP + ATP  UTP +ADP (non-specific enzyme)
Saccharomyces Uridylate kinase
24 kDa monomer EC PDB 1UKZ, 1.9Å
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47. CTP synthetase UTP + gln + ATP  CTP + glu + ADP + Pi
Glutamine side-chain is amine donor
ATP provides energy
 sandwich (Rossmann)
Enzyme is inhibited by CTP
In E.coli, it’s activated by GTP (makes sense!)
E.coli
CTP synthetase 247 kDa tetramer dimer shown
EC PDB 1S1M, 2.3Å
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48. Purine biosynthesis: overview
PRPP + 2 gln + glycine + asp + 5 ATP + 2 N10-formylTHF  11 intermediates to IMP
IMP + asp + GTP  AMP + fumarate + GDP + Pi
IMP + NAD + ATP + gln  GMP + NADH + glu + AMP + PPi
IMP
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49. PRPP + gln to phosphoribosylamine1
PRPP aminated: PRPP + gln  glu + PPi + 5-phospho--D-ribosylamine via glutamine-PRPP amidotransferase
transferase structure
Product is unstable (lasts seconds!)
E.coli GPAT 120 kDa tetramer dimer shown EC PDB 1ECF, 2Å
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50. Phospho- ribosylamine to GAR2
Amine condenses with glycine to form glycinamide ribonucleotide (GAR)
ATP hydrolysis drives GAR synthetase reaction to the right
Geobacillus kaustophilus GARS; EC kDa monomer PDB 2YRX, 1.9Å 2
Glycinamide ribonucleotide
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51. Formylation of GAR 3
10-formyl THF donates a formyl (-CH=O) group to end nitrogen with the help of GAR transformylase to form formylglycinamide ribonucleotide (FGAR)
Rossmann 
Human GAR transformylase 47 kDa dimer EC PDB 1MEO, 1.72 Å
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52. FGAR to FGAM 4
Glutamine sidechain is source of N for C=O exchanging to C=NH via FGAM synthetase to form formylglycinamidine ribonucleotide (FGAM): FGAR + gln + ATP + H2O  FGAM + glu + ADP + Pi
Methanobacterium PurS component of FGAM synthetase 40 kDa tetramer EC PDB 1GTD, 2.56Å
FGAM
FGAM
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53. Aminoimidazole ribonucleotide
FGAM to AIR 5
Cyclize FGAM to aminoimidazole ribonucleotide
ATP drives the AIR synthetase reaction:
FGAM + ATP + H2O  AIR + ADP + Pi
E.C. in Wikipedia was wrong until I caught it
Human AIR synthetase
EC kDa tetramer dimer shown PDB 2V9Y, 2.1Å
Aminoimidazole ribonucleotide
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54. AIR to CAIR 6
AIR is carboxylated; expenditure of an ATP: AIR + HCO3- + ATP  carboxyaminoimidazole ribonucleotide + ADP + Pi + 2H+
AIR carboxylase (no cofactors)
E.coli version is two enzymes; eukaryotes have a single enzyme
E.Coli AIR carboxylase
149 kDa octamer monomer shown EC PDB 2NSH, 2.1Å
CAIR
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55. CAIR+asp to SAICAR 7
CAIR + asp + ATP  aminoimidazole succinylocarboxamide ribonucleotide + ADP + Pi
Enzyme is SAICAR synthetase
Domain 1: homolog of phosphorylase kinase
Domain 2: ATP-binding
SAICAR
yeast SAICAR synthetase 34 kDa monomer EC PDB 2CNQ,1.8Å
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56. SAICAR to AICAR 8
SAICAR  aminoimidazole carboxamide ribonucleotide + fumarate
Enzyme is adenylosuccinate lyase
Net result of two reactions is just replacing acid with amide;
Like 1st 2 reactions in urea cycle, except ADP, not AMP, is the product
E.Coli ASL EC kDa tetramer dimer shown PDB 2PTR, 1.85Å
AICAR
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57. AICAR to FAICAR 9
10-formylTHF donates HC=O: AICAR + 10-formylTHF  formamidoimidazole carboxamide ribonucleotide + THF
Enzyme: AICAR transformylase
Like step 3
Generally a bifunctional enzyme combined with next step
This part is like cytidine deaminase (see below)
Chicken AICAR tranformylase
130 kDa dimer EC
PDB 1THZ, 1.8Å
FAICAR
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58. FAICAR to IMP We made it: FAICAR  inosine 5’-monosphosphate + H2O10
We made it: FAICAR  inosine 5’-monosphosphate + H2O
Bifunctional enzyme; this part is called IMP cyclohydrolase or inosicase
Hydrolase part is like methylglyoxal synthase
Human inosicase EC kDa tetramer dimer shown 1PL0, 2.6Å
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59. So now we have a purine. What next?
Enzymatic conversions to AMP or GMP; Details on next few slides
AMP and GMP can be further phosphorylated to make ADP, GDP with specific kinases (adenylate kinase and guanylate kinase)
GTP made with broad-spectrum nucleoside diphosphate kinase
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60. IMP to adenylosuccinate
IMP + aspartate + GTP  adenylosuccinate + GDP + Pi
Enzyme is adenylosuccinate synthetase
Similar to step 7 in IMP synthesis
human AS Synth. 101 kDa dimer monomer shown EC PDB 2V40, 1.9Å
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61. Adenylosuccinate to AMP
Adenylosuccinate  AMP + fumarate
Like reaction 8 in the IMP pathway; in fact, it uses the same enzyme, adenylosuccinate lyase
Thermatoga ASL 199 kDa tetramer dimer shown PDB 1C3C, 1.8Å
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62. IMP to XMP IMP + H2O + NAD+  Xanthosine monophosphate + NADH + H+
Enzyme: IMP dehydrogenase
TIM-barrel, aldolase-like protein
Tritrichomonas foetus IMPDH
221 kDa tetramer; monomer shown
EC PDB 1ME8, 1.9Å
Xanthosine monophosphate
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63. XMP to GMP Typical 3-layer sandwich
XMP + gln + H2O + ATP  GMP + glu + AMP + PPi
Enzyme: GMP synthetase
Typical 3-layer sandwich
Pyrococcus horikoshii GMP synthetase
68 kDa dimer EC
PDB 2DPL, 1.43Å
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64. Adenylate kinase Reminder: ATP + AMP  2 ADP
Metal ions (Zn2+) play a role in enzyme structure
Enzymes like this need to shield their active sites from water to avoid pointless hydrolysis of ATP
Bacillus stearothermophilus
adenylate kinase
24 kDa monomer EC
PDB 1ZIN, 1.6Å
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65. Guanylate kinase GMP + ATP  GDP + ADP
“P-loop”-containing ATP-binding proteins; there are many P-loop NTPases in molecular motors
Rossmann fold
Often membrane-associated and intimately associated with other functions
Plasmodium vivax guanylate kinase
22 kDa monomer
EC PDB 2QOR, 1.8Å
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66. Purine control I: IMP level
Note that GTP is a cosubstrate in making AMP from IMP
ATP is a cosubstrate in making GMP from IMP
So this helps balance the 2 products
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67. Purine control II: feedback inhibition
PRPP synthetase inhibited by purines, but only at unrealistic concentrations of [Pur]
Step 1 (gln-PRPP amidotransferase) is allosterically inhibited by IMP, AMP, GMP
Adenylosuccinate synthetase is inhibited by AMP
XMP and GMP inhibit IMP dehydrogenase
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68. Making deoxyribonucleotides
Conversions of nucleotides to deoxynucleotides occurs at the diphosphate level
Reichard showed that most organisms have a single ribonucleotide reductase that converts ADP, GDP, CDP, UDP to dADP, dGDP, dCDP, and dUDP
NADPH is the reducing agent
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69. Ribonucleotide reductase heterotetramer
2 RNR1 subunits; each has
a helical 220-aa domain
10-strand 480-aa structure (thiols here)
5-strand 70-aa structure
E.coli RNR1 258 kDa dimer PDB 1R1R 2.9Å
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70. RNR 2 2 RNR2 subunits; each has A diferric ion center
A stable tyrosyl free radical
E.coli RNR2 82 kDa dimer EC PDB 1PJ0, 1.9Å
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