Proton Magnetic Resonance Studies of Folate, Dihydrofolate, and Methotrexate

Poe, Martin

doi:10.1016/s0021-9258(19)43355-3

Cited by 53 publications

(59 citation statements)

References 28 publications

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“…Using our α values, we can predict μ 23 / RT values. For the dimeric folate model proposed by Poe, this value is 0.81 ± 0.03 m –1 . We note the predicted values are based on specific structures of folate while the experimental value describes the solution conformation(s).…”

Section: Discussionmentioning

confidence: 94%

“…Using an NMR approach, Poe found folate dimerization is pH-dependent . The N3–O4 atoms in the pterin ring undergo a keto–enol tautomerization as shown in Figure S1B.…”

Section: Resultsmentioning

confidence: 99%

“…Deprotonation of the enol (p K a ∼ 8) results in a negatively charged O4 atom. The dimerization constant for neutral folate is 20 mM, while the value for basic folate is 340 mM . To potentially determine a μ 23 / RT value for monomeric folate, we repeated the VPO study at pH 10.…”

Section: Resultsmentioning

confidence: 99%

“…As folate dimerizes at high (nonphysiological) concentrations, we additionally monitored the μ 23 / RT value as a function of folate concentration. The data were fit to a dimerization function (eq ) adapted from Duff et al where μ 23 / RT obs is the observed μ 23 / RT , μ 23 / RT (M) and μ 23 / RT (D) are the μ 23 / RT values for the monomer and dimer, respectively, K d is the dimerization constant, and [F] tot is the total folate concentration.…”

Section: Methodsmentioning

confidence: 99%

“…Folate also undergoes a keto–enol tautomerization at the N3–O4 atoms and can deprotonate at the O4 position at high pH . Thus, we studied the effect of pH on the folate μ 23 / RT value.…”

Section: Methodsmentioning

confidence: 99%

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Aspects of Weak Interactions between Folate and Glycine Betaine

et al. 2016

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Folate, or vitamin B9, is an important compound in one-carbon metabolism. Previous studies have found weaker binding of dihydrofolate to dihydrofolate reductase in the presence of osmolytes. In other words, osmolytes are more difficult to remove from the dihydrofolate solvation shell than water; this shifts the equilibrium toward the free ligand and protein species. This study uses vapor-pressure osmometry to explore the interaction of folate with the model osmolyte, glycine betaine. This method yields a preferential interaction potential (μ23/RT value). This value is concentration-dependent as folate dimerizes. The μ23/RT value also tracks the deprotonation of folate’s N3–O4 keto–enol group, yielding a pKa of 8.1. To determine which folate atoms interact most strongly with betaine, the interaction of heterocyclic aromatic compounds (as well as other small molecules) with betaine was monitored. Using an accessible surface area approach coupled with osmometry measurements, deconvolution of the μ23/RT values into α values for atom types was achieved. This allows prediction of μ23/RT values for larger molecules such as folate. Molecular dynamics simulations of folate show a variety of structures from extended to L-shaped. These conformers possess μ23/RT values from −0.18 to 0.09 m–1, where a negative value indicates a preference for solvation by betaine and a positive value indicates a preference for water. This range of values is consistent with values observed in osmometry and solubility experiments. As the average predicted folate μ23/RT value is near zero, this indicates folate interacts almost equally well with betaine and water. Specifically, the glutamate tail prefers to interact with water, while the aromatic rings prefer betaine. In general, the more protonated species in our small molecule survey interact better with betaine as they provide a source of hydrogens (betaine is not a hydrogen bond donor). Upon deprotonation of the small molecule, the preference swings toward water interaction because of its hydrogen bond donating capacities.

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Section: Discussionmentioning

confidence: 94%

“…Using an NMR approach, Poe found folate dimerization is pH-dependent . The N3–O4 atoms in the pterin ring undergo a keto–enol tautomerization as shown in Figure S1B.…”

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

Section: Methodsmentioning

confidence: 99%

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