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Carboplatin binding to histidine.

Tanley SW, Diederichs K, Kroon-Batenburg LM, Levy C, Schreurs AM, Helliwell JR - Acta Crystallogr F Struct Biol Commun (2014)

Bottom Line: Tetragonal HEWL crystals co-crystallized with carboplatin were successfully obtained in four different conditions, each at a different pH value.The structural results obtained show carboplatin bound to either one or both of the N atoms of His15 of HEWL, and this particular variation was dependent on the concentration of anions in the crystallization mixture and the elapsed time, as well as the pH used.The potential impact of the results for the administration of carboplatin as an anticancer agent are described.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Chemistry, Faculty of Engineering and Physical Sciences, University of Manchester, Brunswick Street, Manchester M13 9PL, England.

ABSTRACT
Carboplatin is a second-generation platinum anticancer agent used for the treatment of a variety of cancers. Previous X-ray crystallographic studies of carboplatin binding to histidine (in hen egg-white lysozyme; HEWL) showed the partial conversion of carboplatin to cisplatin owing to the high NaCl concentration used in the crystallization conditions. HEWL co-crystallizations with carboplatin in NaBr conditions have now been carried out to confirm whether carboplatin converts to the bromine form and whether this takes place in a similar way to the partial conversion of carboplatin to cisplatin observed previously in NaCl conditions. Here, it is reported that a partial chemical transformation takes place but to a transplatin form. Thus, to attempt to resolve purely carboplatin binding at histidine, this study utilized co-crystallization of HEWL with carboplatin without NaCl to eliminate the partial chemical conversion of carboplatin. Tetragonal HEWL crystals co-crystallized with carboplatin were successfully obtained in four different conditions, each at a different pH value. The structural results obtained show carboplatin bound to either one or both of the N atoms of His15 of HEWL, and this particular variation was dependent on the concentration of anions in the crystallization mixture and the elapsed time, as well as the pH used. The structural details of the bound carboplatin molecule also differed between them. Overall, the most detailed crystal structure showed the majority of the carboplatin atoms bound to the platinum centre; however, the four-carbon ring structure of the cyclobutanedicarboxylate moiety (CBDC) remained elusive. The potential impact of the results for the administration of carboplatin as an anticancer agent are described.

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The three different forms of His. (a) The protonated form which exists at pH < 6.0, (b) the deprotonated form which exists at physiological pH values between 6.5 and 7.5 and (c) the imidazolyl anion form which exists once both of the N–H atoms have been extracted.
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fig5: The three different forms of His. (a) The protonated form which exists at pH < 6.0, (b) the deprotonated form which exists at physiological pH values between 6.5 and 7.5 and (c) the imidazolyl anion form which exists once both of the N–H atoms have been extracted.

Mentions: As we have explained previously (Tanley, Schreurs, Kroon-Batenburg, Meredith et al., 2012 ▶), and as we briefly reiterate here, the case of binding to both the Nδ and N∊ atoms of His15 could be owing to the His residue being an imidazolyl anion or owing to the histidine being able to exist in two tautomeric forms in solution at a pH similar to the pKa (6.0–6.3). In the case of two tautomeric forms, either the Nδ or the N∊ atom can participate in the interaction with Pt. The imidazolyl anion is formed upon the removal of both of the N–H atoms and can be brought about by a high concentration of Cl− ions (1.4 M) in the co-crystallization conditions used in these studies (Tanley, Schreurs, Kroon-Batenburg, Meredith et al., 2012 ▶). The imidazolyl anion has a lone pair of electrons on both N atoms each capable of bonding to metal atoms. Thus, the His residue is known to be able to exist in three different forms: protonated His at pH <6.0, deprotonated His at physiological pHs between 6.5 and 7.5 and the imidazolyl anion formed by the extraction of the two N–H atoms (Fig. 5 ▶). In our previous studies (Tanley, Schreurs, Kroon-Batenburg & Helliwell, 2012 ▶; Tanley, Schreurs, Kroon-Batenburg, Meredith et al., 2012 ▶; Helliwell & Tanley, 2013 ▶) the overall summed occupancies of the two Pt atoms was greater than 100% and thus it was concluded that an imidazolyl anion was present rather than there being two tautomeric forms.


Carboplatin binding to histidine.

Tanley SW, Diederichs K, Kroon-Batenburg LM, Levy C, Schreurs AM, Helliwell JR - Acta Crystallogr F Struct Biol Commun (2014)

The three different forms of His. (a) The protonated form which exists at pH < 6.0, (b) the deprotonated form which exists at physiological pH values between 6.5 and 7.5 and (c) the imidazolyl anion form which exists once both of the N–H atoms have been extracted.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4157408&req=5

fig5: The three different forms of His. (a) The protonated form which exists at pH < 6.0, (b) the deprotonated form which exists at physiological pH values between 6.5 and 7.5 and (c) the imidazolyl anion form which exists once both of the N–H atoms have been extracted.
Mentions: As we have explained previously (Tanley, Schreurs, Kroon-Batenburg, Meredith et al., 2012 ▶), and as we briefly reiterate here, the case of binding to both the Nδ and N∊ atoms of His15 could be owing to the His residue being an imidazolyl anion or owing to the histidine being able to exist in two tautomeric forms in solution at a pH similar to the pKa (6.0–6.3). In the case of two tautomeric forms, either the Nδ or the N∊ atom can participate in the interaction with Pt. The imidazolyl anion is formed upon the removal of both of the N–H atoms and can be brought about by a high concentration of Cl− ions (1.4 M) in the co-crystallization conditions used in these studies (Tanley, Schreurs, Kroon-Batenburg, Meredith et al., 2012 ▶). The imidazolyl anion has a lone pair of electrons on both N atoms each capable of bonding to metal atoms. Thus, the His residue is known to be able to exist in three different forms: protonated His at pH <6.0, deprotonated His at physiological pHs between 6.5 and 7.5 and the imidazolyl anion formed by the extraction of the two N–H atoms (Fig. 5 ▶). In our previous studies (Tanley, Schreurs, Kroon-Batenburg & Helliwell, 2012 ▶; Tanley, Schreurs, Kroon-Batenburg, Meredith et al., 2012 ▶; Helliwell & Tanley, 2013 ▶) the overall summed occupancies of the two Pt atoms was greater than 100% and thus it was concluded that an imidazolyl anion was present rather than there being two tautomeric forms.

Bottom Line: Tetragonal HEWL crystals co-crystallized with carboplatin were successfully obtained in four different conditions, each at a different pH value.The structural results obtained show carboplatin bound to either one or both of the N atoms of His15 of HEWL, and this particular variation was dependent on the concentration of anions in the crystallization mixture and the elapsed time, as well as the pH used.The potential impact of the results for the administration of carboplatin as an anticancer agent are described.

View Article: PubMed Central - HTML - PubMed

Affiliation: School of Chemistry, Faculty of Engineering and Physical Sciences, University of Manchester, Brunswick Street, Manchester M13 9PL, England.

ABSTRACT
Carboplatin is a second-generation platinum anticancer agent used for the treatment of a variety of cancers. Previous X-ray crystallographic studies of carboplatin binding to histidine (in hen egg-white lysozyme; HEWL) showed the partial conversion of carboplatin to cisplatin owing to the high NaCl concentration used in the crystallization conditions. HEWL co-crystallizations with carboplatin in NaBr conditions have now been carried out to confirm whether carboplatin converts to the bromine form and whether this takes place in a similar way to the partial conversion of carboplatin to cisplatin observed previously in NaCl conditions. Here, it is reported that a partial chemical transformation takes place but to a transplatin form. Thus, to attempt to resolve purely carboplatin binding at histidine, this study utilized co-crystallization of HEWL with carboplatin without NaCl to eliminate the partial chemical conversion of carboplatin. Tetragonal HEWL crystals co-crystallized with carboplatin were successfully obtained in four different conditions, each at a different pH value. The structural results obtained show carboplatin bound to either one or both of the N atoms of His15 of HEWL, and this particular variation was dependent on the concentration of anions in the crystallization mixture and the elapsed time, as well as the pH used. The structural details of the bound carboplatin molecule also differed between them. Overall, the most detailed crystal structure showed the majority of the carboplatin atoms bound to the platinum centre; however, the four-carbon ring structure of the cyclobutanedicarboxylate moiety (CBDC) remained elusive. The potential impact of the results for the administration of carboplatin as an anticancer agent are described.

Show MeSH
Related in: MedlinePlus