I. David Goldman, M.D.
Structure/function, physiological and pharmacological roles of folate transporters and the genetics of hereditary folate malabsorption
Folates are one-carbon donors essential for DNA and RNA synthesis and methylation reactions. There are a variety of folate-deficiency disorders that affect adults, children and infants. Structural analogs of the folates were the first class of anticancer drugs to enter the clinics and remain important components of current cancer therapeutic regimens. This laboratory has had a long-standing interest in the membrane transport of folates and antifolates and the role that transport plays as a determinant of the efficacy of antifolate drugs. Recently, this laboratory cloned the proton-coupled folate transporter (PCFT- SLC46A1), required for the intestinal absorption of folates, and established that there are loss-of-function mutations in this gene in the autosomal recessive disorder, hereditary folate malabsorption (Cell, 127:917-928, 2006; Blood, 110: 1147-1152, 2007). At the present time there are three areas of ongoing research:
(1) Structure-funition studies of PCFT are geared to the identification of residues required for the maintenance of tertiary structure, the translocation pathway, folate and proton binding, and oscillation of the carriers between its conformational states. These studies are informed by analysis of PCFT mutations in patients with HFM, by site-directed mutagenesis and by application of the substituted cysteine accessibility method. Transport studies employ both electrophysiological measurements in Xenopus oocytes and analyses of radiolabeled folate flux determinations in cell lines. The tertiary PCFT structure is being developed using homology modeling based upon bacterial facilitative transporter structures. Representative publications based upon this work include: (J. Biol Chem 284:17846-17857, 2009; Am J Physiol Cell Physiol, 297:C66-74, 2009; Blood 116:5162-9, 2010; J. BioI. Chern. 286:24150-8, 2011; Am. J. of Physiol., Cell Physiol. 302:C1405-12, 2012; Am J Physiol. Cell Physiol., 304:C1159-67, 2013). PCFT is also required for transport of folates into the brain, essential for neural development in infancy. As families are identified world-wide with HFM, and studied in this laboratory, the genetics of this disorder and its manifestations are being characterized along with genotype-phenotype relationships (Mol Genet Metab. 103:33-7, 2011;Gene. 2013 Jun 28.2013, Epub ahead of print). Other studies are exploring regulation of PCFT and the impact of methylation on the expression of this gene (Mol Cancer Ther, 8: 2424-31, 2009).
(2) PCFT is a member of one of seven families of proton-coupled transporters that operate most efficiently at low-pH. These transporters are all required for the absorption of their substrates (peptides, amino acids, monocarboxylic acids, divalent metal ions, etc) in the acidic microclimate of the proximal small intestine. Proton-coupled transporters also mediate export of their substrates from acidified endosomes during receptor-mediated endocytosis. This is also the case for PCFT in a process under study in this laboratory (J Bioi Chem, 284:4267-74, 2009).
(3) Finally, structural analogs of folates are employed for the treatment of cancer and autoimmune diseases. Membrane transport is a key determinant of the effectiveness of these drugs and impaired transport is an important element in drug resistance. Under study are: (i) Pemetrexed, a new generation inhibitor of thymidylate synthase, approved for the treatment of lung cancer and mesothelioma (Current Opinion in Investigational Drugs. 11: 1409-23, 2010). (ii) Pralatrexate, a second-generation dihydrofolate reductase inhibitor. Its cellular pharmacology is being characterized (Cancer Chemother Pharmacol. Jul 24, 2013, Epub ahead of print). A new area of research is focused on a novel class of drugs in which cytotoxics, linked to folic acid, are endocytosed via folate receptors following which the active agent is released within, and diffuses out of, the endosome to reach its intracellular target within tumor cells. Of particular interest is the mechanism by which tumor cells develop resistance to these drugs.
For additional information on publications from this laboratory go to search PubMed: Goldman id.
Recent Reviews from this laboratory
Zhao, R., Matherly, LH., and Goldman ID. Membrane transporters and folate homeostasis: Intestinal absorption, transport into systemic compartments and tissues. Expert Reviews in Molecular Medicine, Cambridge University Press, ePub 11:E4, 2009.
Goldman ID, Chattopadhyay S and Moran R. The Antifolates: Evolution, New Agents in the Clinic, and How Targeting Delivery via Specific Membrane Transporters is Driving Development of a Next Generation of Folate Analogs. Current Opinion in Investigational Drugs. 11:1409-23, 2010.
Zhao R, Diop-Bove N, Visentin M, and Goldman ID. Mechanisms of Membrane Transport of Folates into Cells and Across Epithelia. Annual Review of Nutrition. 31:177-201, 2011.
Diop-Bove N, Kronn D, Goldman ID. Hereditary Folate Malabsorption (December 2011) in: GeneReviews at GeneTests: Medical Genetics Information Resource [database online]. Copyright, University of Washington, Seattle, 1997-2010. Online at: http://www.genetests.org.
Visentin M, Zhao R, Goldman ID. The Antifolates. Hematol Oncol Clin North Am. 26:629-48, 2012.
Zhao R, Goldman ID. Folate and thiamine transporters mediated by facilitative carriers (SLC19A1-3 and SLC46A1) and folate receptors. Mol Aspects Med. 34:373-85, 2013.
Visentin M, Diop-Bove N, Zhao R, Goldman ID. The Intestinal Absorption of Folates. Ann Rev of Physiol. In press, 2013
More Information About Dr. I. David Goldman
Profile for I. David Goldman
Material in this section is provided by individual faculty members who are solely responsible for its accuracy and content.