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PubMed1971

Further observations on the folate-binding factor in some leukemic cells.

The lysates of peripheral cells as well as the serum from some patients with chronic myelogenous leukemia, contained a macromolecular factor which bound tritiated folic acid. Bound tracer folate filtered through Sephadex G-75 and G-100 columns with the early effluent and appeared with the inner volume through a Sephadex G-200 column. Bound tracer could not be extracted from solution by coated charcoal or the anion exchange resin Dowex 2-X8 and could not be reduced to tetrahydrofolate by folate reductase. The velocity of the binding reaction was very rapid and dissociation of bound tracer extremely slow. Binding decreased sharply below pH 5.0 and the binding factor as well as the folate-binder complex, resisted 56 degrees C for 30 min. The binding factor in the leukemic lysate could be separated from endogenous folate reductase by filtration through a G-75 Sephadex column. Competitive inhibition studies demonstrated little or no inhibition of binding of tritiated folic acid by formyltetrahydrofolate and methyltetrahydrofolate. Diopterin (pteroyldiglutamate), pteropterin (pteroyltriglutamate), methotrexate, and dihydrofolate inhibited binding of tracer folate but not as effectively as unlabeled folic acid. The function of this folate binder is unknown. However, that it reacts with dihydrofolate suggests some relationship (physiologic or pathologic) to DNA synthesis since this folate cofactor is essential for the de novo synthesis of thymidylate from deoxyuridylate. In addition, these findings also suggest that the binding of methotrexate may, like folate, inhibit its reaction with folate reductase, and thus be a mechanism by which leukemic cells become resistant to this drug.

Bone Marrow↗
PubMed1987

Identification of high affinity folate binding proteins in human erythrocyte membranes.

Mature human erythrocyte membranes contained specific, high affinity (Kd 3.3 X 10(-11) M) folate binding moieties. Folate binding was pH, time- and temperature-dependent, saturable, and was much greater for pteroylmonoglutamate and 5-methyltetrahydrofolate than 5-formyltetrahydrofolate and amethopterin. On detergent solubilization of membranes, two peaks of specific folate binding with Mr greater than or equal to 200,000 and 160,000 were identified on Sephacryl S-200 gel filtration chromatography in Triton X-100, and this corresponded to two similar peaks of immunoprecipitated material when solubilized iodinated membranes were probed with anti-human placental folate receptor antiserum. Age-dependent separation of erythrocytes by Stractan density gradients revealed a sevenfold greater folate binding capacity in membranes purified from younger compared with aged erythrocytes. Since this difference was not reflected in proportionately higher immunoreactive folate binding protein, (as determined by a specific radioimmunoassay for these proteins), or differences in affinity in younger than aged cells, these findings indicate that erythrocyte folate binding proteins become progressively nonfunctional at the onset of red cell aging.

Carrier Proteins↗
PubMed1988

Influence on immunoreactive folate-binding proteins of extracellular folate concentration in cultured human cells.

The influence of extracellular folate concentration on cellular levels of the folate transport protein and its soluble product was studied directly in cultured human nasopharyngeal carcinoma (KB) cells. As determined by radioimmunoassay, levels of the folate transport protein and the soluble folate-binding protein were 58 +/- 17 (mean +/- SD) and 5 +/- 2 pmol/mg cell protein, respectively, in KB cells maintained in standard medium (containing 2,300 nM folic acid). These levels significantly increased to 182 +/- 34 and 26 +/- 6 pmol/mg cell protein, respectively, in KB cells serially passaged in low folate medium (containing 2-10 nM 5-methyltetrahydrofolate). Increases in folate-binding protein levels occurred more rapidly in KB cells serially passaged in very low folate medium containing less than 2 nM folate and were prevented by the addition of 100 nM 5-methyltetrahydrofolate or 0.1-1 microM 5-formyltetrahydrofolate to this medium. When KB cells which had been passaged in low folate medium were passaged back into either standard medium or low folate medium supplemented with reduced folates, the levels of both folate-binding proteins fell linearly towards the levels in KB cells continuously maintained in standard medium. The folate transport protein was identified in and underwent similar changes in human and mouse mammary tumor cells. These studies indicate that the folate transport system is probably regulated by the extracellular folate concentration through changes in intracellular metabolite levels.

Animals↗
PubMed1989

Bioequivalence of two leucovorin calcium tablet formulations.

In a randomized, single-dose, two-way crossover study, 36 male volunteers received 25 mg each of two oral formulations of leucovorin calcium. Reduced serum folate concentrations were determined over the 24 hours after dosing. There were no statistically significant differences in areas under the serum concentration-time curves for total L-tetrahydrofolates, L-leucovorin (L-5-formyltetrahydrofolate), and L-5-methyltetrahydrofolate (the active metabolite of leucovorin and the predominant circulating form of reduced folate after oral administration). The peak serum concentrations and times to peak serum concentrations were also not significantly different. We conclude that the two leucovorin calcium 5 mg tablet formulations are bioequivalent.

Adult↗
PubMed1986

Phase I and pharmacologic studies of intraperitoneal leucovorin and 5-fluorouracil in patients with advanced cancer.

Many patients with gastrointestinal (GI) tumors develop extensive peritoneal and serosal metastasis and/or malignant ascites which respond poorly to available treatments. Twelve patients with tumors confined primarily to the intraabdominal cavity were treated with intraperitoneal (IP) 5-fluorouracil (5-FU) in escalating concentrations (2 to 4 mmol/L) in combination with leucovorin (dl-5-formyltetrahydrofolic acid or folinic acid; dl-CF) in a 2-L volume, either by eight consecutive four-hour dwells or once daily for five days. CF dose was 20.8 or 104 mumol/L. Nine of the patients had pancreatic carcinoma, one had stomach carcinoma, and two had hepatobiliary neoplasms. Median age was 62.5 years and median Eastern Cooperative Oncology Group (ECOG) performance status was 3. Toxicity included mucositis, diarrhea, nausea and vomiting, leucopenia, skin rash, and abdominal pain, and was similar to that previously reported for IP 5-FU used as a single agent. Four episodes of peritonitis occurred, but all patients responded to antibiotics. At the 20.8 mumol/L dose, dl-CF concentration in the peritoneal fluid declined from 10.4 +/- 3.0 3.0 mumol/L at one hour to 4.9 +/- 2.2 mumol/L at four hours, corresponding to a mean absorption half-life of 127 +/- 49 minutes and a mean peritoneal clearance of 13.0 +/- 4.5 mL/min. Decline was biphasic in all but five of the 19 exchanges evaluated. The levels of l-CF (biologically active isomer of dl-CF) were 2.8 +/- 2.5 mumol/L after 60 minutes and 1.2 +/- 0.7 mumol/L after four hours. The peritoneal area under the concentration v time curve (AUC) for 5-FU increased proportionally with dose. For example, the AUC at 2.0 and 3.5 mmol/L was 129 +/- 25 and 201 +/- 23 mmol/L X minute, respectively. However, the maximal peritoneal to plasma AUC ratio was 461 at the 2 mmol/L dose, but decreased with increasing doses as systemic clearance decreased. This regimen was well tolerated in patients with advanced cancer, but must be evaluated further to determine its clinical efficacy.

Abdominal Neoplasms↗
PubMed1987

A phase II trial of 5-fluorouracil and high-dose intravenous leucovorin in gastric carcinoma.

Twenty-eight patients with advanced measurable gastric carcinoma were treated with leucovorin (dl-CF; folinic acid; dl-5-formyltetrahydrofolic acid) 500 mg/m2 administered as a two-hour infusion and 5-fluorouracil (5-FU) 600 mg/m2 intravenous (IV) push midinfusion. Treatment was administered weekly for 6 weeks followed by a 2-week rest. Twenty-five patients were evaluable for response. Twelve of them had received previous combination chemotherapy that included 5-FU. Median age was 59 years, and median Eastern Cooperative Oncology Group (ECOG) performance status was 2. Three patients had partial responses and two of them had been treated previously with 5-FU. Twelve patients had stable disease. Five of these patients had subjective improvement with improved performance status and/or decreased dysphagia. The 95% confidence interval for response is 3% to 32%. Median survival time for all 28 patients enrolled in the study was 22 weeks. Toxicity was moderate and consisted primarily of diarrhea. Myelosuppression, skin rash, and increased lacrimation also occurred. Plasma concentrations of the active reduced folates, I-CF and 5-methyltetrahydrofolic acid (5-CH3FH4), were greater than the 10 mumol/L levels that potentiate 5-FU activity in in vitro models, for more than four hours in all five patients in whom pharmacokinetics were studied. 5-FU and high-dose dl-CF has activity in patients with gastric carcinoma including patients who had previously progressed on 5-FU-containing combinations. Further study in a larger patient population is necessary to determine the usefulness of this regimen in gastric carcinoma.

Adenocarcinoma↗
PubMed2005

Corynebacterium sp. U-96 contains a cluster of genes of enzymes for the catabolism of sarcosine to pyruvate.

The sarcosine oxidase gene and nearby genes from Corynebacterium sp. U-96 were determined. The genes for serine hydroxymethyltransferase, the beta, delta, alpha, and gamma subunits of sarcosine oxidase, serine dehydratase, and 10-formyltetrahydrofolate hydrolase are arranged in this order. This suggests that the bacteria contain a cluster of genes for the catabolism of sarcosine to pyruvate. The possibility that the gene cluster is a merit for the cellular energy demands of the bacteria is discussed. Functional expression of sarcosine oxidase in Escherichia coli was accomplished, but the beta subunit and the betadelta complex were expressed at a low level as a soluble protein.

Bacterial Proteins↗
PubMed2003

Determination of folate vitamers in human serum by stable-isotope-dilution tandem mass spectrometry and comparison with radioassay and microbiologic assay.

BACKGROUND: Current clinical methods for folate give different results and cannot measure the various forms of folate. We developed an isotope-dilution tandem mass spectrometric method coupled to liquid chromatography (LC/MS/MS) as a candidate reference method for 5-methyltetrahydrofolic acid (5MeTHF), 5-formyltetrahydrofolic acid (5FoTHF), and folic acid (FA) in human serum. METHODS: We quantitatively isolated folates from 275 microL of serum with a phenyl solid-phase extraction cartridge, then detected and quantified them in stabilized serum extracts by positive-ion electrospray ionization LC/MS/MS. We used an isocratic mobile phase of acetic acid in organic solvent on a C(8) analytical column. (13)C-labeled folates were used as internal standards. RESULTS: Limits of detection in serum were 0.13 (5MeTHF), 0.05 (5FoTHF), and 0.07 (FA) nmol/L. Within- and between-run imprecision (CV) was <7% for 5MeTHF and <10% for 5FoTHF at concentrations >0.5 nmol/L, and <10% for FA at concentrations >2.0 nmol/L. Total folate (TFOL) concentrations determined by competitive protein binding radioassay were approximately 9% lower than results obtained with LC/MS/MS. The microbiologic assay gave approximately 15% higher TFOL results with FA calibrator and no difference with 5MeTHF calibrator. The mean (SD) [range] TFOL in 42 sera was 35.5 (17.8) [6.5-75.6] nmol/L. Thirty-two samples with TFOL <50 nmol/L had, on average, 93.3% 5MeTHF, 2.3% FA, and 4.4% 5FoTHF. Ten samples with TFOL >50 nmol/L had, on average, 81.7% 5MeTHF, 15.7% FA, and 2.5% 5FoTHF. CONCLUSIONS: This stable-isotope-dilution LC/MS/MS method can quantify 5MeTHF, 5FoTHF, and FA in serum. Currently used clinical assays agree with this candidate reference method.

Autoanalysis↗
PubMed1985

Drugs and folate metabolism.

Folates are a group of compounds which are required in the diet and are important in DNA, amino acids and possibly also amine metabolism. The biologically active folates are in the tetrahydro form. Tetrahydrofolates are produced from unreduced dietary folates by the enzyme dihydrofolate reductase. A number of drugs such as aminopterin, methotrexate (amethopterin), pyrimethamine, trimethoprim and triamterene act as folate antagonists and produce folate deficiency by inhibiting this enzyme. With other drugs which produce low serum and tissue concentrations of folate such as anticonvulsants, antituberculosis drugs, alcohol and oral contraceptives, the mechanism of this effect is uncertain. Possible mechanism include reduced absorption, prevention of release of folate from tissue stores, altered plasma protein binding, or increased folate metabolism in the liver. Treatment with folic acid antagonists such as methotrexate readily causes megaloblastic anaemia; this can be prevented by therapy with folinic acid (5-formyltetrahydrofolate). The role of other drugs in producing megaloblastic anaemia is less certain, e.g. it occurs in less than 0.75% of patients receiving anticonvulsants. The possible neurological and psychiatric effects of folate deficiency are also uncertain. However, in patients with folate deficiency who have neuropsychiatric symptoms, neuropathy or myelopathy, and normal vitamin B12 levels, it may be of value to try therapy with folic or folinic acid.

Amines↗
PubMed1982

The effects of nitrous oxide on cobalamins, folates, and on related events.

The anaesthetic gas nitrous oxide (N2O), when inhaled for longer than 6 hr, produces megaloblastic anemia in man. Longer term inhalation, as in addicts, produces a syndrome similar to that due to B12 neuropathy, and long term exposure to low concentrations results in an increased abortion rate and neuropathy, particularly in dental personnel. N2O acts by oxidizing vitamin B12 from the active reduced cob[I]alamin form to the inactive cob[III]alamin form. In turn, this inactivates the enzyme methionine synthetase which requires both B12 and folate as cofactors. In the rat, hepatic methionine synthetase is completely inactivated after 3 hr exposure to a mixture of equal parts of N2O/O2. There is an impared uptake of folate analogues by the liver so that the plasma folate level rises and thereafter there is a considerable loss of folate into the urine. Hepatic folate concentration falls to 25% within 10 days of N2O exposure. There is a failure to synthesize folate polyglutamate (the active folate coenzyme) from all other than formyltetrahydrofolate. As oxidization of the methyl of methionine is an important source of formyl, the failure of methionine synthesis in turn appears to lead to the failure in supply of formate and, hence, a lack of the formylfolate substrate.

5-Methyltetrahydrofolate-Homocysteine S-Methyltran↗
PubMed1992

Membrane transport of folate compounds.

All eukaryotic cells and some prokaryotes that are unable to synthesize folic acid utilize membrane-associated transport systems for acquisition of the pre-formed vitamin or its coenzyme forms from external sources. These transport systems, in addition to providing folates essential for cell replication, are also important because of their role in the internalization of antifolates such as Methotrexate (MTX) that are used extensively in cancer chemotherapy. Information about the components and mechanism of folate transport systems has been derived, in large part, from studies with Lactobacillus casei and L1210 mouse leukemia cells, which serve as convenient models for prokaryotes and eukaryotes, respectively. L. casei contain a single folate transport system whose Kt value (i.e., concentration for half-maximum rate of uptake) for the preferred substrate folate is in the nanomolar range. The hydrophobic membrane-associated folate transport protein (18 kDa) has been purified to homogeneity and characterized. Expression of this transporter is repressed in cells grown on high concentrations (microM) of folate. L1210 cells contain two separate transport systems for folate compounds: (1) the low affinity system (Kt values for the preferred substrates 5-methyl- and 5-formyltetrahydrofolate and MTX in the microM range); and (2) the high affinity system (Kt for folate in the nM range). Fluorescein and biotin derivatives of MTX and folate, after conversion to N-hydroxysuccinimide esters, can be attached covalently to the transporters. These probes have been used for visualizing the transporters by fluorescence and electron microscopy and for their purification to homogeneity.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed2001

Comparison of dihydrofolate reductase activities for folic acid in pigs and rats using in vivo and in vitro evaluation techniques.

The activity of dihydrofolate reductase (DHFR) for folic acid (PteGlu) was evaluated in pigs by in vivo and in vitro experiments. The results were compared with those of rats. Since bile secretion of reduced folates reflects the activity of DHFR for PteGlu in the body, the bile secretion rates of reduced folates including tetrahydrofolate (H4PteGlu), 5-methyltetrahydrofolate, 5,10-methylenetetrahydrofolate, and 10-formyltetrahydrofolate were determined by using high-performance liquid chromatography with electrochemical detection, after the intravenous injection of PteGlu at 1 mg/kg body weight to pigs and rats. Although the PteGlu injection raised the total secretion rate of reduced folates. the total increased amount of reduced folates secreted into bile from 0 h to 2.5 h after PteGlu injection in pigs was about one-tenth of that in rats. The enzyme kinetics of DHFR for PteGlu was examined at the physiological condition (pH 7.4 and 3 7 degrees C). Affinity chromatography was applied to liver homogenates of pigs and rats to obtain DHFR. The final product of the enzyme reaction, H4PteGlu, was measured. The Km for pig enzyme was similar to that for rat enzyme, whereas the Vmax for the pig enzyme was less than 1/5 of that for the rat's. The comparison of the ratio of Vmax to Km between pig and rat enzymes suggests that PteGlu is a much less efficient substrate for pig liver DHFR. In short, these results from in vivo and in vitro experiments suggest that the role of DHFR for PteGlu in pigs is physiologically much less important than that in rats.

Animals↗
PubMed1987

Phosphate-induced phosphoribosylpyrophosphate elevations to assess deranged folate and purine nucleotide metabolism.

Phosphoribosylpyrophosphate (PRPP) levels increase several-fold in HL-60 cells adapted to folate deficiency either by continuous passage in folate-deficient medium or by short-term incubation with 10(-8) M methotrexate (MTX). The addition of folic acid (PteGlu) or 5-formyltetrahydrofolic acid (5-CHO-H4PteGlu) in the form of Leucovorin normalizes this effect. The reactions for measuring PRPP levels are time and temperature dependent and are influenced by PRPP-reacting substances in undialyzed serum. Inorganic phosphate (PO4), when added to the assay, markedly stimulates PRPP levels in HL-60 cells and can be used to stress folate-dependent PRPP utilization for purine synthesis. The integrity of the folate-dependent pathways of purine-synthesizing cells can be sensitively assessed by measurement of PRPP levels during a 2-hr assay in the presence of PO4 in medium free of folate but containing dialyzed serum. In HL-60 cells that are folate deficient or in the presence of MTX (as low as 2 X 10(-9) M), PO4-stimulated PRPP levels remain elevated due to ineffective utilization unless folate is added to the incubation mixture. The sensitivity of this PRPP assay to metabolically assess the integrity of folate-dependent reactions in purine synthesis is comparable to that of the deoxyuridine suppression assay. Inorganic phosphate can also be used to stimulate the incorporation of purine analogs, such as 6-mercaptopurine, into intact red blood cells which may have therapeutic implications for targeting drug delivery.

Cell Line↗
PubMed1993

Transport of folates and antifolates in liver.

The characteristics and mechanisms of hepatic transport of folates and antifolate cancer drugs, for example, methotrexate, have been studied in perfused liver, isolated hepatocytes (in both freshly isolated cells and in primary cell culture), and membrane vesicles isolated from the basolateral membrane. Both naturally occurring folates and antifolates are taken up by the perfused liver and secreted into bile by apparently active processes, since these compounds are concentrated in liver and bile compared with the perfusate. Transport of the naturally occurring folate 5-methyltetrahydrofolate in isolated hepatocytes and basolateral membrane vesicles is via cotransport with hydrogen ions, is electroneutral, and is inhibitable by other reduced folates and by methotrexate. Transport of methotrexate is by a multispecific anion carrier, is electrogenic, and is not inhibitable by reduced folates (e.g., 5-methyl- and 5-formyltetrahydrofolate). Thus, the hepatocyte has separate systems for uptake of the naturally occurring, reduced folates and for the 4-amino-substituted antifolates.

Animals↗
PubMed1996

Biochemical and Molecular Studies of Human Methenyltetrahydrofolate Synthetase.

5-FormylH(4)folate is administered clinically under the name Leucovorintrade mark in association with the antineoplastic agent 5-fluorouracil (5-FU) to enhance the cytotoxic effects of 5-FU. The combination has been shown to be superior to 5-FU alone in the treatment of patients with metastatic colorectal carcinoma. Methenyltetrahydrofolate synthetase (MTHFS) catalyzes the transformation of 5-formyltetrahydrofolate to methenylH(4)folate, which is the obligatory initial metabolic step prior to the intracellular conversion of 5-formylH(4)folate to other reduced folates and the increase in intracellular folate pools required for 5-FU potentiation. In the following paper, we will summarize results of biochemical and molecular studies of human MTHFS.

Journal Article↗
PubMed2000

Role of the amino acid 45 residue in reduced folate carrier function and ion-dependent transport as characterized by site-directed mutagenesis.

In previous reports, an E45K mutation in reduced folate carrier (RFC1) resulted in marked substrate-specific changes in folate binding and the induction of an obligatory inorganic anion requirement for carrier function. In this study, site-directed mutagenesis was employed to further characterize the role of glutamate-45 in carrier function by replacement with glutamine, arginine, aspartate, leucine, or tryptophan followed by tranfection of the mutated cDNAs into the MTX(r)A line, which lacks a functional endogenous carrier. Alterations in transport function with amino acid substitutions at this residue were not charge related. Hence, E45Q, E45R, and E45K all 1) increased carrier affinity for 5-formyltetrahydrofolate approximately 4-fold, 2) increased affinity for folic acid approximately 6- to 10-fold, 3) did not change affinity for 5-methyltetrahydrofolate, and 4) except for E45R decreased affinity for methotrexate (2- to 3-fold). In contrast, mutations E45D, E45L, and E45W generally reduced affinity for all these folates except for folic acid. Finally, chloride-dependent influx was only noted in the E45R mutant. These data further substantiate the important role that glutamate-45 plays in the selectivity of binding of folates to RFC1 and establish that it is the addition of a positive charge at this site and not the loss of a negative charge that results in the induced anion dependence. These and other studies indicate that mutations in the first transmembrane domain can have a markedly selective impact on the affinity of RFC1 for folate compounds and in particularly a highly salutary effect on binding of the oxidized folate, folic acid.

Amino Acid Substitution↗
PubMed2000

The mechanism of transport of the multitargeted antifolate (MTA) and its cross-resistance pattern in cells with markedly impaired transport of methotrexate.

MTA (LY231514) is an antifolate that targets multiple folate-dependent enzymes. In this report, MTA transport was characterized in wild-type L1210 cells and variants with impaired membrane transport or polyglutamation. MTA influx via the reduced folate carrier was somewhat faster (approximately 30%) than that for methotrexate (MTX). Unlike MTX, MTA was rapidly polyglutamated in L1210 cells; hence, a folylpoly-gamma-glutamate synthetase-deficient L1210 variant was used to assess net transport and efflux properties. The MTA transmembrane gradient for exchangeable drug was 2.5 times greater than the MTX gradient, attributable primarily to an efflux rate constant 40% that of MTX. No MTA was bound to dihydrofolate reductase. When grown with folic acid, MTX-resistant L1210 variants with mutations in the reduced folate carrier demonstrated cross-resistance to MTA, markedly reduced MTA accumulation, and only a slightly decreased intracellular folate cofactor pool as compared to L1210 cells. However, when 5-formyltetrahydrofolate was the growth substrate, these MTX-resistant cells were less resistant or negligibly resistant to MTA, accumulated more MTA, and had a lower folate pool as compared to L1210 cells. MTA activity and the intracellular folate pool in L1210 cells were inversely related. These data indicate that MTA polyglutamation in L1210 cells is favored by both the generation of high intracellular drug levels and high MTA affinity for FPGS relative to MTX. Cells resistant to MTX because of impaired transport may retain appreciable sensitivity to MTA because of a concurrent reduction in tetrahydrofolate cofactor transport resulting in cellular folate depletion, which diminishes endogenous folate suppression of MTA polyglutamation.

Animals↗
PubMed1975

The heterogeneity and properties of folate binding proteins from chronic myelogenous leukemia cells.

Previous studies have demonstrated that some chronic myelogenous leukemia cells contain a macromolecular binding factor for folic acid. This binder, which previously was believed to be a single factor, has now been resolved into two distinct binding proteins. Separation of each binder was obtained by DEAE chromatography of the partially purified lysate of chronic myelogenous leukemia cells. One binder has a molecular weight of 30;000-35,000, and the second binder has a molecular weight of 40,000-45,000. Both proteins bind the mono-, di-, and triglutamates of folic acid, N10-methyl-folate, dihydro-folate, and N5-methyltetrahydrofolate. Neither binder has determinants for N5-formyltetrahydrofolate or methotrexate. The preferred substrates for both binders appear to be the fully oxidized and partially reduced folates rather than the fully reduced folates. The lower-molecular-weight folate binding protein shows reversible binding with partially and fully reduced folates but irreversible binding with oxidized folates. This property suggests that this binder may have some function in the transport and storage of folate. The higher-molecular-weight folate binding protein, however, has only slight reversibility of binding with the partially and fully reduced folates, and it is therefore more difficult to postulate a physiologic function for this binding factor.

Carrier Proteins↗