Literature summary for 2.4.2.1 extracted from

  • Wierzchowski, J.; Stachelska-Wierzchowska, A.; Wielgus-Kutrowska, B.; Bzowska, A.
    1,N6-ethenoadenine and other fluorescent nucleobase analogs as substrates for purine-nucleoside phosphorylases Spectroscopic and kinetic studies (2017), Curr. Pharm. Des., 23, 6948-6966 .
    View publication on PubMed

Application

Application Comment Organism
pharmacology substrate 6-mercaptopurine-2'-deoxyriboside is of special interest, because, in contrast to a nucleoside, its parent purine is highly cytotoxic and is known as one of the first compounds applied as anti-cancer drugs Escherichia coli
drug development the enzyme is a target for drug development Helicobacter pylori
drug development differences in specificity between homotrimeric (including human enzyme) and homohexameric PNPs, including various pathogenic organisms, make them interesting potential drug targets Bos taurus
drug development differences in specificity between homotrimeric (including human enzyme) and homohexameric PNPs, including various pathogenic organisms, make them interesting potential drug targets Escherichia coli
drug development differences in specificity between homotrimeric (including human enzyme) and homohexameric PNPs, including various pathogenic organisms, make them interesting potential drug targets Homo sapiens
drug development the enzyme is a target for development of anti-malarial drugs Plasmodium falciparum

Engineering

Protein Variants Comment Organism
N243D site-directed mutagenesis, the mutation in trimeric PNP changes the substrate specificity, making 6-aminopurine nucleosides good substrates Thermus thermophilus
N243D site-directed mutagenesis, the mutation in trimeric PNP changes the substrate specificity, making 6-aminopurine nucleosides good substrates Bos taurus
N243D site-directed mutagenesis, the mutation in trimeric PNP changes the substrate specificity, making 6-aminopurine nucleosides good substrates Homo sapiens

Inhibitors

Inhibitors Comment Organism Structure
6-methylformycin A strng inhibition Escherichia coli
9-(3-pyridylmethyl)-9-deaza-guanosine i.e. peldesine or BCX34 Bos taurus
9-(3-pyridylmethyl)-9-deaza-guanosine i.e. peldesine or BCX34 Homo sapiens
DADMe-immucillin-G i.e. forodesine or BCX4945 Bos taurus
DADMe-immucillin-G i.e. forodesine or BCX4945 Homo sapiens
DADMe-immucillin-G i.e. forodesine or BCX4945 Plasmodium falciparum
DADMe-immucillin-H i.e. ulodesine or BCX4208 Bos taurus
DADMe-immucillin-H i.e. ulodesine or BCX4208 Homo sapiens
DADMe-immucillin-H i.e. ulodesine or BCX4208 Plasmodium falciparum
DATMe-immucillin-H
-
Bos taurus
DATMe-immucillin-H
-
Homo sapiens
DFPP-DG
-
Bos taurus
DFPP-DG
-
Homo sapiens
Formycin A an analogue of adenosine Bos taurus
Formycin A
-
Escherichia coli
Formycin A an analogue of adenosine Homo sapiens
formycin B structural, 9-deaza-8-aza analogue of inosine Bos taurus
formycin B structural, 9-deaza-8-aza analogue of inosine Escherichia coli
formycin B structural, 9-deaza-8-aza analogue of inosine Homo sapiens
immucillin-G an analogue of guanosine Bos taurus
immucillin-G an analogue of guanosine Homo sapiens
immucillin-H i.e. forodesine or BCX1777, an analogue of inosine Bos taurus
immucillin-H i.e. forodesine or BCX1777, an analogue of inosine Homo sapiens
additional information formycins are 9-deaza-8-aza-nucleosides and selective inhibitors of hexameric PNPs. 8-Aza-9-deazapurine derivatives as enzyme inhibitors, overview Escherichia coli
additional information immucillins are potent slow-binding inhibitors, forming rapidly the enzyme/inhibitor collision complex that is characterized by nM enzyme/inhibitor affinity, followed by a slow conformational change leading a tight-binding enzyme/inhibitor complex. Immucilins, like ground-state analogue inhibitors, bind with the stoichiometry of three molecules per enzyme trimer. Another interesting class of PNP inhibitors comprises so-called bisubstrate analogs, represented by purine-alkylphosphonates and difluoromethylene phosphonates, which compete with both PNP substrates, nucleoside and phosphate, and therefore interact with PNP with inhibition constants markedly dependent on inorganic phosphate concentration. 8-aza-9-deazapurine derivatives as enzyme inhibitors, overview Homo sapiens
SerMe-immucillin-H SerMe-ImmH, uses achiral dihydroxyaminoalcohol seramide as the ribocation mimic Bos taurus
SerMe-immucillin-H SerMe-ImmH, uses achiral dihydroxyaminoalcohol seramide as the ribocation mimic Homo sapiens

Natural Substrates/ Products (Substrates)

Natural Substrates Organism Comment (Nat. Sub.) Natural Products Comment (Nat. Pro.) Rev. Reac.
inosine + phosphate Thermus thermophilus
-
hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate Bacillus cereus
-
hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate Pectobacterium carotovorum
-
hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate Plasmodium lophurae
-
hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate Cellulomonas sp.
-
hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate Bos taurus
-
hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate Escherichia coli
-
hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate Plasmodium falciparum
-
hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate Homo sapiens
-
hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate Helicobacter pylori
-
hypoxanthine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate Thermus thermophilus
-
guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate Bacillus cereus
-
guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate Pectobacterium carotovorum
-
guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate Plasmodium lophurae
-
guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate Cellulomonas sp.
-
guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate Bos taurus
-
guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate Escherichia coli
-
guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate Plasmodium falciparum
-
guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate Homo sapiens
-
guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate Helicobacter pylori
-
guanine + alpha-D-ribose 1-phosphate
-
r
adenosine + phosphate Escherichia coli
-
adenine + alpha-D-ribose 1-phosphate
-
r
nicotinamide riboside + phosphate Escherichia coli
-
nicotinamide + alpha-D-ribose 1-phosphate
-
r
8-azaguanine + alpha-D-ribose 1-phosphate Escherichia coli
-
8-azaguanosine + phosphate
-
r
1-methyladenosine + phosphate Escherichia coli
-
1-methyladenine + alpha-D-ribose 1-phosphate
-
r
1-methylguanosine + phosphate Escherichia coli
-
1-methylguanine + alpha-D-ribose 1-phosphate
-
r
6-mercaptopurine-2'-deoxyriboside + phosphate Escherichia coli
-
6-mercaptopurine + 2-deoxy-alpha-D-ribose 1-phosphate
-
r
8-azaguanosine + phosphate Escherichia coli
-
8-azaguanine + alpha-D-ribose 1-phosphate
-
r
8-azaguanosine + phosphate Homo sapiens
-
8-azaguanine + alpha-D-ribose 1-phosphate
-
r
9-beta-D-arabinosyl-2-fluoroadenine + phosphate Escherichia coli i.e. fludarabine 2-fluoroadenine + beta-D-arabinose 1-phosphate
-
r
xanthosine + phosphate Escherichia coli
-
xanthine + alpha-D-ribose 1-phosphate
-
r

Organism

Organism UniProt Comment Textmining
Bacillus cereus
-
-
-
Pectobacterium carotovorum
-
-
-
Thermus thermophilus
-
-
-
Plasmodium lophurae
-
-
-
Helicobacter pylori A0A518Y5Z2 multifunctional fusion protein
-
Homo sapiens P00941
-
-
Escherichia coli P0ABP8
-
-
Escherichia coli P45563
-
-
Bos taurus P55859 calf
-
Cellulomonas sp. P81989
-
-
Plasmodium falciparum Q8I3X4
-
-

Source Tissue

Source Tissue Comment Organism Textmining
erythrocyte
-
Homo sapiens
-
blood high PNP level Homo sapiens
-

Substrates and Products (Substrate)

Substrates Comment Substrates Organism Products Comment (Products) Rev. Reac.
additional information hexameric PNPs accept as substrates many nucleoside analogues with various modifications in the purine ring, with an important exception of 7-deaza nucleosides. N7-Methylated guanosine, inosine and adenosine are unusual fluorescent substrates of both trimeric and hexameric PNPs Escherichia coli ?
-
-
additional information N1-methylated guanosine, inosine, and adenosine derivatives are selective substrates for hexameric PNP from Escherichia coli. Hexameric PNPs accept as substrates many nucleoside analogues with various modifications in the purine ring, with an important exception of 7-deaza nucleosides. N7-Methylated guanosine, inosine and adenosine are unusual fluorescent substrates of both trimeric and hexameric PNPs. Escherichia coli PNP converts pro-drugs, which are relative nontoxic purine nucleosides (for example 6-methyl purine 2'-deoxynucleoside or fludarabine), to their respective purine analogs (here, to 6-methylpurine and 2-fluoroadenine, respectively), which are very potent, toxic drugs. Enzymatic ribosylation of 8-azapurines, overview. Isoadenosine (3-beta-D-ribosyl-adenine), is, unlike the parent adenosine, a quite good substrate for mammalian and bacterial PNP. Ribosylation of tri-cyclic nucleobase analogues and phosphorolysis Escherichia coli ?
-
-
additional information nicotinamide riboside is a substrate of trimeric PNPs because it mimics 6-keto/N1H arrangement of 6-oxopurine nucleosides and 8-azaguanine. For trimeric PNP, the proton at the purine position N1 is required for catalysis. N7-Methylated guanosine, inosine and adenosine are unusual fluorescent substrates of both trimeric and hexameric PNPs. No activity with pro-drugs 6-methyl purine 2'-deoxynucleoside or fludarabine (9-beta-D-arabinosyl-2-fluoroadenine). Enzymatic ribosylation of 8-azapurines, overview. Isoadenosine (3-beta-D-ribosyl-adenine), is, unlike the parent adenosine, a quite good substrate for mammalian and bacterial PNP. Ribosylation of tri-cyclic nucleobase analogues and phosphorolysis Homo sapiens ?
-
-
additional information the hexamric PNP binds adenosine but it does not catalyze its phosphorolysis Thermus thermophilus ?
-
-
additional information the trimeric PNP binds adenosine but it does not catalyze its phosphorolysis Cellulomonas sp. ?
-
-
inosine + phosphate
-
Thermus thermophilus hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate
-
Bacillus cereus hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate
-
Pectobacterium carotovorum hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate
-
Plasmodium lophurae hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate
-
Cellulomonas sp. hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate
-
Bos taurus hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate
-
Escherichia coli hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate
-
Plasmodium falciparum hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate
-
Homo sapiens hypoxanthine + alpha-D-ribose 1-phosphate
-
r
inosine + phosphate
-
Helicobacter pylori hypoxanthine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate
-
Thermus thermophilus guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate
-
Bacillus cereus guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate
-
Pectobacterium carotovorum guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate
-
Plasmodium lophurae guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate
-
Cellulomonas sp. guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate
-
Bos taurus guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate
-
Escherichia coli guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate
-
Plasmodium falciparum guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate
-
Homo sapiens guanine + alpha-D-ribose 1-phosphate
-
r
guanosine + phosphate
-
Helicobacter pylori guanine + alpha-D-ribose 1-phosphate
-
r
adenosine + phosphate
-
Escherichia coli adenine + alpha-D-ribose 1-phosphate
-
r
nicotinamide riboside + phosphate
-
Escherichia coli nicotinamide + alpha-D-ribose 1-phosphate
-
r
8-azaguanine + alpha-D-ribose 1-phosphate
-
Escherichia coli 8-azaguanosine + phosphate
-
r
1-methyladenosine + phosphate
-
Escherichia coli 1-methyladenine + alpha-D-ribose 1-phosphate
-
r
1-methylguanosine + phosphate
-
Escherichia coli 1-methylguanine + alpha-D-ribose 1-phosphate
-
r
6-mercaptopurine-2'-deoxyriboside + phosphate
-
Escherichia coli 6-mercaptopurine + 2-deoxy-alpha-D-ribose 1-phosphate
-
r
8-azaguanosine + phosphate
-
Escherichia coli 8-azaguanine + alpha-D-ribose 1-phosphate
-
r
8-azaguanosine + phosphate
-
Homo sapiens 8-azaguanine + alpha-D-ribose 1-phosphate
-
r
9-beta-D-arabinosyl-2-fluoroadenine + phosphate i.e. fludarabine Escherichia coli 2-fluoroadenine + beta-D-arabinose 1-phosphate
-
r
xanthosine + phosphate
-
Escherichia coli xanthine + alpha-D-ribose 1-phosphate
-
r
1,N6-ethenoadenosine + phosphate i.e. 3-beta-D-ribosylimidazo[2,l-i]purine Escherichia coli 1,N6-ethenoadenine + beta-D-ribose 1-phosphate
-
r
2,6-diamino-8-azapurine + alpha-D-ribose 1-phosphate PNP mutant D204N Bos taurus N7-D-ribosyl-2,6-diamino-8-azapurine + phosphate
-
r
2,6-diamino-8-azapurine + alpha-D-ribose 1-phosphate
-
Bos taurus N8-D-ribosyl-2,6-diamino-8-azapurine + phosphate
-
r
2,6-diamino-8-azapurine + alpha-D-ribose 1-phosphate PNP mutant D204N Bos taurus N9-D-ribosyl-2,6-diamino-8-azapurine + phosphate
-
r

Subunits

Subunits Comment Organism
homotetramer the enzyme is an exception since PNPs are almost all homotrimers or homohexamers Bacillus cereus
homodimer the enzyme is an exception since PNPs are almost all homotrimers or homohexamers Pectobacterium carotovorum
homohexamer
-
Escherichia coli
homohexamer trimer of dimers Escherichia coli
homotrimer
-
Bos taurus
homotrimer
-
Homo sapiens
homopentamer the enzyme is an exception since PNPs are almost all homotrimers or homohexamers Plasmodium lophurae
homotrimer or homohexamer the hexamer is a trimer of dimers Thermus thermophilus
homotrimer or homohexamer the hexamer is a trimer of dimers Cellulomonas sp.

Synonyms

Synonyms Comment Organism
DeoD
-
Escherichia coli
PNP
-
Thermus thermophilus
PNP
-
Bacillus cereus
PNP
-
Pectobacterium carotovorum
PNP
-
Plasmodium lophurae
PNP
-
Cellulomonas sp.
PNP
-
Bos taurus
PNP
-
Escherichia coli
PNP
-
Plasmodium falciparum
PNP
-
Homo sapiens
PNP
-
Helicobacter pylori
PNP-II
-
Escherichia coli
xapA
-
Escherichia coli
xanthosine phosphorylase
-
Escherichia coli
XAP
-
Escherichia coli
punA
-
Cellulomonas sp.

Ki Value [mM]

Ki Value [mM] Ki Value maximum [mM] Inhibitor Comment Organism Structure
0.1
-
formycin B pH and temperature not specified in the publication Homo sapiens
0.0003
-
6-methylformycin A pH and temperature not specified in the publication Escherichia coli
0.005
-
formycin B pH and temperature not specified in the publication Escherichia coli
0.000000009
-
DADMe-immucillin-H pH and temperature not specified in the publication Homo sapiens
0.000000009
-
DATMe-immucillin-H pH and temperature not specified in the publication Homo sapiens
0.000000005
-
SerMe-immucillin-H pH and temperature not specified in the publication Homo sapiens
0.0000044
-
DFPP-DG pH and temperature not specified in the publication Bos taurus
0.000000023
-
DADMe-immucillin-H pH and temperature not specified in the publication Bos taurus
0.0000135
-
9-(3-pyridylmethyl)-9-deaza-guanosine pH and temperature not specified in the publication Homo sapiens
0.000000058
-
immucillin-H pH and temperature not specified in the publication Homo sapiens

Expression

Organism Comment Expression
Escherichia coli Escherichia coli PNP-II (xanthosine phosphorylase) is inducible by xanthosine up

General Information

General Information Comment Organism
physiological function Escherichia coli PNP converts pro-drugs, which are relative nontoxic purine nucleosides (for example 6-methyl purine 2'-deoxynucleoside or fludarabine), to their respective purine analogues (here, to 6-methylpurine and 2-fluoroadenine, respectively), which are very potent, toxic drugs Escherichia coli
malfunction substrate specificity of trimeric and hexameric PNPs may be changed by mutations of the crucial active site amino acids, namely Asp in hexameric PNPs and Asn in trimeric PNPs Thermus thermophilus
malfunction substrate specificity of trimeric and hexameric PNPs may be changed by mutations of the crucial active site amino acids, namely Asp in hexameric PNPs and Asn in trimeric PNPs Cellulomonas sp.
malfunction substrate specificity of trimeric and hexameric PNPs may be changed by mutations of the crucial active site amino acids, namely Asp in hexameric PNPs and Asn in trimeric PNPs Bos taurus
malfunction substrate specificity of trimeric and hexameric PNPs may be changed by mutations of the crucial active site amino acids, namely Asp in hexameric PNPs and Asn in trimeric PNPs Escherichia coli
malfunction substrate specificity of trimeric and hexameric PNPs may be changed by mutations of the crucial active site amino acids, namely Asp in hexameric PNPs and Asn in trimeric PNPs Homo sapiens
evolution in some organisms, like Escherichia coli, two distinct forms of PNP exist, with markedly different structure and substrate specificity. The second form, the so-called E. coli PNP-II, is sometimes referred to as xanthosine phosphorylase, since it is inducible by this nucleoside, but its specificity is not limited to this compound, and includes guanosine, inosine and nicotinamide riboside Escherichia coli
evolution in some organisms, like Escherichia coli, two distinct forms of PNP exist, with markedly different structure and substrate specificity. The second form, the so-called Escherichia coli PNP-II, is sometimes referred to as xanthosine phosphorylase, since it is inducible by this nucleoside, but its specificity is not limited to this compound, and includes guanosine, inosine and nicotinamide riboside Escherichia coli
evolution the homodimeric PNP from Ervinia carotovora cannot be assigned to the two described PNP classes, trimeric and hexameric PNPs Pectobacterium carotovorum
evolution the homotetrameric PNP from Baccilus cereus cannot be assigned to the two described PNP classes, trimeric and hexameric PNPs Bacillus cereus
evolution the pentameric PNP from Plasmodium lophurae cannot be assigned to the two described PNP classes, trimeric and hexameric PNPs Plasmodium lophurae
evolution the PNP from Cellulomonas sp. cannot be assigned to the any of two described PNP classes, trimeric and hexameric PNPs Cellulomonas sp.
evolution the PNP from Thermus thermophilus cannot be assigned to the any of two described PNP classes, trimeric and hexameric PNPs Thermus thermophilus