Difference between revisions of "Transformation of PGH2 to PGE2"
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[[Welcome to the In-Silico Model of Cutaneous Lipids Wiki | Return to overview]] | [[Welcome to the In-Silico Model of Cutaneous Lipids Wiki | Return to overview]] | ||
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+ | PGE2 is produced by the isomerisation of the PGH2 peroxide, into a ketone at C9 and an alcohol at C11 by PGES, yielding PGE2. This reaction is catalysed by isoforms of PGES, such as cPGES (also known as PGES-3), mPGES-1 and mPGES-2 <ref>Samuelsson, B. Morgenstern, R. Jakobsson, P. J. , ''Membrane prostaglandin E synthase-1: a novel therapeutic target'', Pharmacol Rev (2007), 59, 207-24.</ref>. cPGES is the cytosolic isoform of PGES which is constitutively expressed in the cytosol of various cells <ref>Tanioka, T. Nakatani, Y. Semmyo, N. Murakami, M. Kudo, I., ''Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis'', J Biol Chem (2000), 275, 32775-82.</ref>, whereas mPGES-1/-2 are Golgi membrane-associated proteins which only become cytosolic following spontaneous cleavage of a hydrophobic domain <ref>Murakami, M. Nakashima, K. Kamei, D. Masuda, S. Ishikawa, Y. Ishii, T. Ohmiya, Y. Watanabe, K. Kudo, I., ''Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2'', J Biol Chem (2003), 278, 37937-47.</ref><ref>Tanioka, T. Nakatani, Y. Semmyo, N. Murakami, M. Kudo, I., ''Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis'', J Biol Chem (2000), 275, 32775-82.</ref>. It has been suggested that a functional coupling of cPGES and COX-1 may occur in vitro as cPGES appears to convert only COX-1 derived PGH2 and not COX-2 derived PGH2 <ref>Tanioka, T. Nakatani, Y. Semmyo, N. Murakami, M. Kudo, I., ''Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis'', J Biol Chem (2000), 275, 32775-82.</ref>. Interestingly, the opposite has been observed for mPGES and COX-2 <ref>Murakami, M. Nakashima, K. Kamei, D. Masuda, S. Ishikawa, Y. Ishii, T. Ohmiya, Y. Watanabe, K. Kudo, I., ''Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2'', J Biol Chem (2003), 278, 37937-47.</ref>. | ||
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+ | |||
== Reaction == | == Reaction == | ||
[[File:R10_PGH2_-_PGE2.jpg|center|500px]] | [[File:R10_PGH2_-_PGE2.jpg|center|500px]] | ||
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==Chemical equation== | ==Chemical equation== | ||
− | <center><math> | + | <center><math> PGH2 \rightleftharpoons PGE2 </math></center> |
== Rate equation == | == Rate equation == | ||
+ | [[File:R10.PNG|center|500px]] | ||
− | + | == Parameters == | |
− | == | + | === K<sub>ms</sub> === |
− | |||
{|class="wikitable sortable" | {|class="wikitable sortable" | ||
− | |+ style="text-align: left;" | | + | |+ style="text-align: left;" | Literature values |
|- | |- | ||
! Value | ! Value | ||
Line 19: | Line 23: | ||
! Species | ! Species | ||
! Notes | ! Notes | ||
+ | ! Weight | ||
! Reference | ! Reference | ||
|- | |- | ||
Line 24: | Line 29: | ||
|<math> mM </math> | |<math> mM </math> | ||
|Human | |Human | ||
− | | | + | |Expression Vector: E. Coli |
+ | Enzyme: PGES | ||
+ | pH: 8 | ||
+ | Temperature: 37 | ||
+ | |512 | ||
|<ref name="Pettersson2005"> [http://www.ncbi.nlm.nih.gov/pubmed/16399384 Pettersson P. , "Identification of beta-trace as prostaglandin D synthase.'' FASEB J. 2010 Dec;24(12):4668-77. doi: 10.1096/fj.10-164863. Epub 2010 Jul 28.]</ref> | |<ref name="Pettersson2005"> [http://www.ncbi.nlm.nih.gov/pubmed/16399384 Pettersson P. , "Identification of beta-trace as prostaglandin D synthase.'' FASEB J. 2010 Dec;24(12):4668-77. doi: 10.1096/fj.10-164863. Epub 2010 Jul 28.]</ref> | ||
|- | |- | ||
Line 31: | Line 40: | ||
|Human | |Human | ||
|Wild Type Enzyme | |Wild Type Enzyme | ||
+ | |1024 | ||
|<ref name="Hamza2010"> [http://www.ncbi.nlm.nih.gov/pubmed/20369883 Hamza A. , "Understanding microscopic binding of human microsomal prostaglandin E synthase-1 (mPGES-1) trimer with substrate PGH2 and cofactor GSH: insights from computational alanine scanning and site-directed mutagenesis.'' J Phys Chem B. 2010 Apr 29;114(16):5605-16. doi: 10.1021/jp100668y.]</ref> | |<ref name="Hamza2010"> [http://www.ncbi.nlm.nih.gov/pubmed/20369883 Hamza A. , "Understanding microscopic binding of human microsomal prostaglandin E synthase-1 (mPGES-1) trimer with substrate PGH2 and cofactor GSH: insights from computational alanine scanning and site-directed mutagenesis.'' J Phys Chem B. 2010 Apr 29;114(16):5605-16. doi: 10.1021/jp100668y.]</ref> | ||
|- | |- | ||
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|<math> mM </math> | |<math> mM </math> | ||
|Human | |Human | ||
− | |cPGES, casein kinase II and Hsp90 | + | |Expression Vector: E. Coli |
+ | Enzyme: PGES | ||
+ | pH: Unknown | ||
+ | Temperature: Unknown | ||
+ | |||
+ | Other: cPGES, casein kinase II and Hsp90 | ||
+ | |64 | ||
|<ref name="Kobayashi04"> [http://www.ncbi.nlm.nih.gov/pubmed/15040786 Kobayashi T. , "Regulation of cytosolic prostaglandin E synthase by phosphorylation.'' Biochem J. 2004 Jul 1;381(Pt 1):59-69.]</ref> | |<ref name="Kobayashi04"> [http://www.ncbi.nlm.nih.gov/pubmed/15040786 Kobayashi T. , "Regulation of cytosolic prostaglandin E synthase by phosphorylation.'' Biochem J. 2004 Jul 1;381(Pt 1):59-69.]</ref> | ||
|- | |- | ||
Line 42: | Line 58: | ||
|<math> mM </math> | |<math> mM </math> | ||
|Human | |Human | ||
− | | | + | |Expression Vector: E. Coli |
+ | Enzyme: PGES | ||
+ | pH: Unknown | ||
+ | Temperature: Unknown | ||
+ | |64 | ||
|<ref name="Kobayashi04"></ref> | |<ref name="Kobayashi04"></ref> | ||
|- | |- | ||
|} | |} | ||
+ | {| class="wikitable" | ||
+ | |+ style="text-align: left;" | Description of the PGES Kms distribution | ||
+ | ! Mode (mM) !! Confidence Interval !! Location parameter (µ) !! Scale parameter (σ) | ||
+ | |- | ||
+ | | 1.97E-01 || 1.73E+00 || -1.39E+00 || 4.91E-01 | ||
+ | |} | ||
+ | |||
+ | [[Image:29.jpg|none|thumb|500px|The estimated probability distribution for PGES Kms. The value and weight of the literature values used to define the distribution are indicated by an orange dashed line. The x axis is plotted on a log-scale. ]] | ||
+ | |||
+ | === K<sub>mp</sub>=== | ||
+ | This is a “Dependent parameter”, meaning that the log-normal distribution for this parameter was calculated using multivariate distributions (this is discussed in detail[[Quantification of parameter uncertainty | here]]). As a result, no confidence interval factor or literature values were cited for this parameter. | ||
+ | {| class="wikitable" | ||
+ | |+ style="text-align: left;" | Description of the PGES Kmp distribution | ||
+ | ! Mode (mM) !! Location parameter (µ) !! Scale parameter (σ) | ||
+ | |- | ||
+ | | 1.93E-01 || -1.15E+00 || 7.02E-01 (mM) | ||
+ | |} | ||
+ | |||
+ | [[Image:30.jpg|none|thumb|500px|The estimated probability distribution for PGES Kmp. The value and weight of the literature values used to define the distribution are indicated by an orange dashed line. The x axis is plotted on a log-scale. ]] | ||
+ | |||
+ | === k<sub>cat</sub>=== | ||
{|class="wikitable sortable" | {|class="wikitable sortable" | ||
− | |+ style="text-align: left;" | | + | |+ style="text-align: left;" | Literature values |
|- | |- | ||
! Value | ! Value | ||
Line 54: | Line 95: | ||
! Species | ! Species | ||
! Notes | ! Notes | ||
+ | ! Weight | ||
! Reference | ! Reference | ||
|- | |- | ||
Line 59: | Line 101: | ||
| per minute | | per minute | ||
| Human | | Human | ||
− | | Microsomal Prostaglandin E Synthase | + | |Expression Vector: E. Coli. |
+ | Enzyme: Microsomal Prostaglandin E Synthase | ||
+ | pH: 7.5 | ||
+ | Temperature: 37 | ||
+ | |1024 | ||
| <ref name="Pettersson20005"> [www.ncbi.nlm.nih.gov/pubmed/16399384 Pettersson P., "Human microsomal prostaglandin E synthase 1: a member of the MAPEG protein superfamily.'' Methods Enzymol. 2005;401:147-61.]</ref> | | <ref name="Pettersson20005"> [www.ncbi.nlm.nih.gov/pubmed/16399384 Pettersson P., "Human microsomal prostaglandin E synthase 1: a member of the MAPEG protein superfamily.'' Methods Enzymol. 2005;401:147-61.]</ref> | ||
|- | |- | ||
|} | |} | ||
+ | |||
+ | {| class="wikitable" | ||
+ | |+ style="text-align: left;" | Description of the PGES kcat distribution | ||
+ | ! Mode (min-1) !! Confidence Interval !! Location parameter (µ) !! Scale parameter (σ) | ||
+ | |- | ||
+ | | 2.98E+03 || 1.13E+00 || 8.01E+00 || 1.19E-01 | ||
+ | |} | ||
+ | |||
+ | [[Image:31.jpg|none|thumb|500px|The estimated probability distribution for PGES kcat. The value and weight of the literature values used to define the distribution are indicated by an orange dashed line. The x axis is plotted on a log-scale. ]] | ||
+ | |||
+ | === Enzyme concentration === | ||
+ | |||
+ | To convert the enzyme concentration from ppm to mM, the following [[Common equations#Enzyme concentration (mM)|equation]] was used. | ||
{|class="wikitable sortable" | {|class="wikitable sortable" | ||
− | |+ style="text-align: left;" | | + | |+ style="text-align: left;" | Literature values |
|- | |- | ||
! Value | ! Value | ||
Line 71: | Line 130: | ||
! Species | ! Species | ||
! Notes | ! Notes | ||
+ | ! Weight | ||
! Reference | ! Reference | ||
|- | |- | ||
− | | | + | |220 |
− | | | + | |<math> ppm </math> |
+ | |Human | ||
+ | |Expression Vector: Placenta | ||
+ | Enzyme: PGES | ||
+ | pH: 7.5 | ||
+ | Temperature: 37 °C | ||
+ | |1024 | ||
+ | |<ref name="Wilhelm2014"> [http://www.nature.com/nature/journal/v509/n7502/pdf/nature13319.pdf M. Wilhelm ''Mass-spectrometry-based draft of the human proteome'' Nature, 2014 509, 582–587]</ref> | ||
+ | |- | ||
+ | |75.3 | ||
+ | |<math> ppm </math> | ||
+ | |Human | ||
+ | |Expression Vector: Urinary Bladder | ||
+ | Enzyme: PGES | ||
+ | pH: 7.5 | ||
+ | Temperature: 37 °C | ||
+ | |1024 | ||
+ | |<ref name="Kim2014"> [http://www.nature.com/nature/journal/v509/n7502/pdf/nature13302.pdf M. Kim ''A draft map of the human proteome'' Nature, 2014 509, 575–581]</ref> | ||
+ | |- | ||
+ | |208 | ||
+ | |<math> ppm </math> | ||
+ | |Human | ||
+ | |Expression Vector: Stomach | ||
+ | Enzyme: PGES | ||
+ | pH: 7.5 | ||
+ | Temperature: 37 °C | ||
+ | |1024 | ||
+ | |<ref name="Wilhelm2014"> [http://www.nature.com/nature/journal/v509/n7502/pdf/nature13319.pdf M. Wilhelm ''Mass-spectrometry-based draft of the human proteome'' Nature, 2014 509, 582–587]</ref> | ||
+ | |- | ||
+ | |28.1 | ||
+ | |<math> ppm </math> | ||
+ | |Human | ||
+ | |Expression Vector: Lung | ||
+ | Enzyme: PGES | ||
+ | pH: 7.5 | ||
+ | Temperature: 37 °C | ||
+ | |1024 | ||
+ | |<ref name="Kim2014"> [http://www.nature.com/nature/journal/v509/n7502/pdf/nature13302.pdf M. Kim ''A draft map of the human proteome'' Nature, 2014 509, 575–581]</ref> | ||
+ | |- | ||
+ | |11.6 | ||
+ | |<math> ppm </math> | ||
|Human | |Human | ||
− | | | + | |Expression Vector: Colon |
− | + | Enzyme: PGES | |
− | |<ref name=" | + | pH: 7.5 |
+ | Temperature: 37 °C | ||
+ | |1024 | ||
+ | |<ref name="Kim2014"> [http://www.nature.com/nature/journal/v509/n7502/pdf/nature13302.pdf M. Kim ''A draft map of the human proteome'' Nature, 2014 509, 575–581]</ref> | ||
+ | |- | ||
+ | |} | ||
+ | |||
+ | {| class="wikitable" | ||
+ | |+ style="text-align: left;" | Description of the PGES concentration distribution | ||
+ | ! Mode (ppm) !! Mode (mM) !! Confidence Interval !! Location parameter (µ) !! Scale parameter (σ) | ||
+ | |- | ||
+ | | 7.49E+01 ||4.15E-04 || 3.15E+00 || 5.03E+00 || 8.44E-01 | ||
+ | |} | ||
+ | |||
+ | [[Image:162.jpg|none|thumb|500px|The estimated probability distribution for PGES concentration. The value and weight of the literature values used to define the distribution are indicated by an orange dashed line. The x axis is plotted on a log-scale. ]] | ||
+ | |||
+ | === K<sub>eq </sub> === | ||
+ | |||
+ | {|class="wikitable sortable" | ||
+ | |+ style="text-align: left;" | Gibbs Free Energy Change | ||
+ | |- | ||
+ | ! Value | ||
+ | ! Units | ||
+ | ! Species | ||
+ | ! Notes | ||
+ | ! Weight | ||
+ | ! Reference | ||
|- | |- | ||
− | | | + | |5.72 |
− | | | + | |kcal/mol |
− | | | + | |Not stated |
− | | | + | |Estimated |
− | |<ref name=" | + | Enzyme: PGES |
+ | Substrate: Arachidonate | ||
+ | Product: PGE2 | ||
+ | pH: 7.3 | ||
+ | ionic strength: 0.25 | ||
+ | |64 | ||
+ | |<ref name="MetaCyc”>[http://metacyc.org/META/NEW-IMAGE?type=REACTION&object=PROSTAGLANDIN-E-SYNTHASE-RXN Caspi et al 2014, "The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of Pathway/Genome Databases," Nucleic Acids Research 42:D459-D471]</ref> | ||
+ | |} | ||
+ | |||
+ | {| class="wikitable" | ||
+ | |+ style="text-align: left;" | Description of the PGES Keq distribution | ||
+ | ! Mode !! Confidence Interval !! Location parameter (µ) !! Scale parameter (σ) | ||
|- | |- | ||
+ | | 7.46E+04 || 1.00E+01 || 1.20E+01 || 8.90E-01 | ||
|} | |} | ||
+ | |||
+ | [[Image:32.jpg|none|thumb|500px|The estimated probability distribution for PGES Keq. The value and weight of the literature values used to define the distribution are indicated by an orange dashed line. The x axis is plotted on a log-scale. ]] | ||
== References == | == References == |
Latest revision as of 07:48, 21 August 2019
PGE2 is produced by the isomerisation of the PGH2 peroxide, into a ketone at C9 and an alcohol at C11 by PGES, yielding PGE2. This reaction is catalysed by isoforms of PGES, such as cPGES (also known as PGES-3), mPGES-1 and mPGES-2 [1]. cPGES is the cytosolic isoform of PGES which is constitutively expressed in the cytosol of various cells [2], whereas mPGES-1/-2 are Golgi membrane-associated proteins which only become cytosolic following spontaneous cleavage of a hydrophobic domain [3][4]. It has been suggested that a functional coupling of cPGES and COX-1 may occur in vitro as cPGES appears to convert only COX-1 derived PGH2 and not COX-2 derived PGH2 [5]. Interestingly, the opposite has been observed for mPGES and COX-2 [6].
Contents
Reaction
Chemical equation
Rate equation
Parameters
Kms
Value | Units | Species | Notes | Weight | Reference |
---|---|---|---|---|---|
1.6E-01 ± 4.00E-03 | Human | Expression Vector: E. Coli
Enzyme: PGES pH: 8 Temperature: 37 |
512 | [7] | |
2.15E-01 | Human | Wild Type Enzyme | 1024 | [8] | |
1.49E-02 | Human | Expression Vector: E. Coli
Enzyme: PGES pH: Unknown Temperature: Unknown Other: cPGES, casein kinase II and Hsp90 |
64 | [9] | |
6.66E-02 | Human | Expression Vector: E. Coli
Enzyme: PGES pH: Unknown Temperature: Unknown |
64 | [9] |
Mode (mM) | Confidence Interval | Location parameter (µ) | Scale parameter (σ) |
---|---|---|---|
1.97E-01 | 1.73E+00 | -1.39E+00 | 4.91E-01 |
Kmp
This is a “Dependent parameter”, meaning that the log-normal distribution for this parameter was calculated using multivariate distributions (this is discussed in detail here). As a result, no confidence interval factor or literature values were cited for this parameter.
Mode (mM) | Location parameter (µ) | Scale parameter (σ) |
---|---|---|
1.93E-01 | -1.15E+00 | 7.02E-01 (mM) |
kcat
Value | Units | Species | Notes | Weight | Reference |
---|---|---|---|---|---|
3000 ± 360 | per minute | Human | Expression Vector: E. Coli.
Enzyme: Microsomal Prostaglandin E Synthase pH: 7.5 Temperature: 37 |
1024 | [10] |
Mode (min-1) | Confidence Interval | Location parameter (µ) | Scale parameter (σ) |
---|---|---|---|
2.98E+03 | 1.13E+00 | 8.01E+00 | 1.19E-01 |
Enzyme concentration
To convert the enzyme concentration from ppm to mM, the following equation was used.
Value | Units | Species | Notes | Weight | Reference |
---|---|---|---|---|---|
220 | Human | Expression Vector: Placenta
Enzyme: PGES pH: 7.5 Temperature: 37 °C |
1024 | [11] | |
75.3 | Human | Expression Vector: Urinary Bladder
Enzyme: PGES pH: 7.5 Temperature: 37 °C |
1024 | [12] | |
208 | Human | Expression Vector: Stomach
Enzyme: PGES pH: 7.5 Temperature: 37 °C |
1024 | [11] | |
28.1 | Human | Expression Vector: Lung
Enzyme: PGES pH: 7.5 Temperature: 37 °C |
1024 | [12] | |
11.6 | Human | Expression Vector: Colon
Enzyme: PGES pH: 7.5 Temperature: 37 °C |
1024 | [12] |
Mode (ppm) | Mode (mM) | Confidence Interval | Location parameter (µ) | Scale parameter (σ) |
---|---|---|---|---|
7.49E+01 | 4.15E-04 | 3.15E+00 | 5.03E+00 | 8.44E-01 |
Keq
Value | Units | Species | Notes | Weight | Reference |
---|---|---|---|---|---|
5.72 | kcal/mol | Not stated | Estimated
Enzyme: PGES Substrate: Arachidonate Product: PGE2 pH: 7.3 ionic strength: 0.25 |
64 | [13] |
Mode | Confidence Interval | Location parameter (µ) | Scale parameter (σ) |
---|---|---|---|
7.46E+04 | 1.00E+01 | 1.20E+01 | 8.90E-01 |
References
- ↑ Samuelsson, B. Morgenstern, R. Jakobsson, P. J. , Membrane prostaglandin E synthase-1: a novel therapeutic target, Pharmacol Rev (2007), 59, 207-24.
- ↑ Tanioka, T. Nakatani, Y. Semmyo, N. Murakami, M. Kudo, I., Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis, J Biol Chem (2000), 275, 32775-82.
- ↑ Murakami, M. Nakashima, K. Kamei, D. Masuda, S. Ishikawa, Y. Ishii, T. Ohmiya, Y. Watanabe, K. Kudo, I., Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2, J Biol Chem (2003), 278, 37937-47.
- ↑ Tanioka, T. Nakatani, Y. Semmyo, N. Murakami, M. Kudo, I., Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis, J Biol Chem (2000), 275, 32775-82.
- ↑ Tanioka, T. Nakatani, Y. Semmyo, N. Murakami, M. Kudo, I., Molecular identification of cytosolic prostaglandin E2 synthase that is functionally coupled with cyclooxygenase-1 in immediate prostaglandin E2 biosynthesis, J Biol Chem (2000), 275, 32775-82.
- ↑ Murakami, M. Nakashima, K. Kamei, D. Masuda, S. Ishikawa, Y. Ishii, T. Ohmiya, Y. Watanabe, K. Kudo, I., Cellular prostaglandin E2 production by membrane-bound prostaglandin E synthase-2 via both cyclooxygenases-1 and -2, J Biol Chem (2003), 278, 37937-47.
- ↑ Pettersson P. , "Identification of beta-trace as prostaglandin D synthase. FASEB J. 2010 Dec;24(12):4668-77. doi: 10.1096/fj.10-164863. Epub 2010 Jul 28.
- ↑ Hamza A. , "Understanding microscopic binding of human microsomal prostaglandin E synthase-1 (mPGES-1) trimer with substrate PGH2 and cofactor GSH: insights from computational alanine scanning and site-directed mutagenesis. J Phys Chem B. 2010 Apr 29;114(16):5605-16. doi: 10.1021/jp100668y.
- ↑ 9.0 9.1 Kobayashi T. , "Regulation of cytosolic prostaglandin E synthase by phosphorylation. Biochem J. 2004 Jul 1;381(Pt 1):59-69.
- ↑ [www.ncbi.nlm.nih.gov/pubmed/16399384 Pettersson P., "Human microsomal prostaglandin E synthase 1: a member of the MAPEG protein superfamily. Methods Enzymol. 2005;401:147-61.]
- ↑ 11.0 11.1 M. Wilhelm Mass-spectrometry-based draft of the human proteome Nature, 2014 509, 582–587
- ↑ 12.0 12.1 12.2 M. Kim A draft map of the human proteome Nature, 2014 509, 575–581
- ↑ Caspi et al 2014, "The MetaCyc database of metabolic pathways and enzymes and the BioCyc collection of Pathway/Genome Databases," Nucleic Acids Research 42:D459-D471