Folic acid: crystal structure and implications for enzyme binding.

The crystal and molecular structure of folic acid dihydrate has been determined by x-ray diffraction. Folic acid is in an extended conformation with the pteridine ring in the keto form. The C(4) oxygen and N(10) atoms are on the same side of the molecule, hydrogen-bonded to the same water. This conformation has the pteridine rotated approximately 180 degrees away from the orientation of the pteridine ring of methotrexate bound to dihydrofolate reductase. The folic acid pteridine and phenyl rings interact in a stacking manner which is suggestive of the type of associations these groups could form in a complex of folate, dihydrofolate reductase, and reduced nicotinamide adenine dinucleotide phosphate.