Structure/function, physiological and pharmacological roles of folate transporters and the genetics of hereditary folate malabsorption
This laboratory has had a long-standing interest in the membrane transport of folates and antifolate cancer chemotherapeutics. 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;Ann Rev Physiol 76:251-74,2014) ). Areas of research: (1) PCFT structure/function: This encompasses the identification of residues and domains required for the maintenance of tertiary structure, the translocation pathway, folate and proton binding, and oscillation of the carrier between its conformational state. (2) Transport energetics: We recently established that PCFT-mediated transport at neutral pH, in the absence of a proton gradient, is concentrative. Ongoing studies are exploring the energetics of this process. (3) Mechanisms of resistance to antifolates that utilize PCFT for transport into tumor cells. Drugs are being developed that are selectively transported by PCFT within the acidic microenvironment of tumors. These studies explore the alterations in PCFT-mediated transported associated with acquired resistance to these agents due to impaired transport. Studies employ both electrophysiological and substrate transport measurements in Xenopus oocytes and analyses of radiolabeled folate flux determinations in cell lines. A three-dimensional homology model of PCFT is being developed in conjunction with the functional studies. (4) As families are identified world-wide with hereditary folate malabsorption, the functional consequences of causative PCFT mutations are studied along with their relationship to the clinical phenotype.
Trainees emerge from this laboratory with a broad understanding of membrane transport physiology along with the cellular, biochemical and molecular pharmacology of cancer chemotherapeutics with a focus on antifolates.
Selected Recent Publications (Complete publications at PubMed: Goldman ID)
Zhao R, Unal E, Shin D, Goldman ID. Membrane topological analyses of the proton-coupled folate transporter (PCFT-SLC46A1) by the substituted cysteine accessibility method. Biochemistry 49:2925-2931, 2010. PMCID:PMC2866095
Shin DS, Min SH, Russell L, Zhao R, Fiser A and Goldman ID. Functional roles of aspartate residues of the human proton-coupled folate transporter (PCFT; SLC46A1); D156, mutated in hereditary folate malabsorption, is critical for protein stability; D109 is irreplaceable. Blood116:5162-9, 2010. PMCID:PMC3012536
Mahadeo K, Bove-Diop N, Ramirez S, Cadilla CL, Rivera E, Martin M, Lerner N B,Santiago-Borrero BJ, and Goldman ID. Prevalence of a loss-of-function founder mutation in the Proton-Coupled Folate Transporter Gene (PCFT-SLC46A1) causing Hereditary Folate Malabsorption in Puerto Rico. J. Pediatrics. 159:623-627,2011. PMCID:PMC3935241.
Zhao R, Shin DS, Diop-Bove N, Ovits CG and Goldman ID Random mutagenesis of the proton-coupled folate transporter (PCFT, SLC46A1), clustering of base deletion/insertion mutations and mechanisms underlying loss-of-function mutations. J. Biol. Chem. 286:24150-8, 2011 PMCID: PMC3129196
Shin DS, Zhao R, Yap EH, Fiser A, Goldman ID. A P425R mutation of the proton-coupled folate transporter causing hereditary folate malabsorption produces a highly selective alteration in folate binding. Am. J. of Physiol., Cell Physiol. 302):C1405-12, 2012. PMCID: PMC3361945
Visentin M, Zhao R, Goldman ID. Augmentation of reduced folate carrier-mediated folate/antifolate transport through an antiport mechanism with 5-aminoimidazole-4-carboxamide riboside monophosphate. Mol Pharmacol. 82:209-16, 2012. PMCID:PMC3400841
Shin DS, Zhao R, Fiser A Goldman ID. The role of the fourth transmembrane domain in proton-coupled folate transporter (PCFT-SLC46A1) function as assessed by the substituted cysteine accessibility method. Am J Physiol. Cell Physiol. 304:C1159-67, 2013. PMCID:PMC3680650
Zhao R, Diop-Bove N, Goldman ID, Enhanced Receptor-mediated Endocytosis and Cytotoxicity of a Folic Acid-desacetylvinblastine Monohydrazide Conjugate in a Pemetrexed-Resistant Cell Line Lacking Folate-specific Facilitative Carriers but with Increased Folate Receptor Expression. Mol. Pharmacol. 85:310-21, 2014. PMCID: PMC3913358.
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.
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. 76:251-74, 2014. PMCID:PMC 3982215.
Diop-Bove N, Kronn D, Goldman ID. Hereditary Folate Malabsorption. 2008 Jun 17 [Updated 2014 Jun 5]. In: Pagon RA, Adam MP, Ardinger HH, et al., editors. GeneReviews® [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2014. Available from: http://www.ncbi.nlm.nih.gov/books/NBK1673/
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