The biological chemistry of folate receptors.

HE ESSENTIAL role of intracellular folates in ef-T fecting one-carbon transfers in critical enzyme systems for DNA synthesis is well This has led to extensive application of various synthetic folate analogues as therapeutic and investigative tools in a variety of infectious, immunologic, and neoplastic diseases, as well as in developmental, transplantation, and tumor b i o l ~ g y. ~ , ~ While the enzyme dihydrofolate reductase (DHFR), the major target for the antifolate, methotrexate (MTX), is a paradigm for many aspects of biologic chemistry and molecular b i o l ~ g y , ~ ~ ~ the use of MTX is also prototypical in clinical medicine. However, cells develop resistance to MTX by DHFR gene amplification/generation of a form of DHFR with an altered affinity (K,,,), failure to polygluta-mate MTX, and a transport defect in intracellular e n t ~. ~-l ~ Whereas the advanced understanding of DHFR and the first two resistance mechanisms is archetypical in oncology, understanding the mechanism of the transport defect for MTX can only be made once details on the cellular uptake of folate is known. Another compelling reason to study folate transport arises from the potentially unique properties of folates as small M,-500, hydrophilic, anionic molecules that must transverse the hydrophobic barrier of the external plasma membrane; from a teleologic point of view, it appears reasonable to speculate that specific mechanisms must exist to assure a constant availability of folates for DNA synthesis. Clinical observations wherein folate-deficient mothers deliver infants with normal folate stores and the existence of a 30-to 100-fold higher red blood cell (RBC) folate content than serum supports a physiologic role for folate transport across the placenta and into RBCs, respecti~ely.~~~J5 In contrast, the syndromes of congenital folate malabsorption16 and familial aplastic anemiaI7 are " experiments of nature " that indicate a congenital and acquired failure in physiologic folate transport, respectively .'~~ Thus, folate transport into cells for intrinsic cellular utilization is to be distinguished from transcellular folate transport across cellular barriers, and the mechanisms involved in these two transport processes will not necessarily be identical. Significant recent advances on the components and mechanism(s) of the cellular uptake of folates in human and primate cells promise to shed new light on these and related clinical observations and form the focus of this review. Other related reviews with a different focus have been published.18-Z4 Oxidized-folic acid (pteroylmonoglutamic acid, PteGlu) …