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Departments of
* Nutritional Science and Dietetics, and
** Biochemistry, University of Nebraska at Lincoln, Lincoln, NE and the
Center for Nutritional Sciences, Food Science and Human Nutrition Department, University of Florida, Gainesville, FL
2To whom correspondence should be addressed. E-mail: jzempleni2{at}unl.edu.
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ABSTRACT |
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 TOP ABSTRACT MATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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also depends on biotin. Biotin metabolites are structurally similar to biotin, and their concentrations in tissues are quantitatively important. Here, the hypothesis was tested that biotin metabolites can mimic the effects of biotin on gene expression and thus have biotin-like activities. A human T-cell line (Jurkat cells) was used to model effects of biotin and synthetic metabolites (diaminobiotin and desthiobiotin) on the expression of genes encoding IL-2 and IL-2R. Cells were cultured in biotin-deficient medium (0.025 nmol/L biotin) for 35 d; controls were cultured in medium containing 10 nmol/L biotin. The biotin-deficient medium was supplemented with 10 nmol/L of diaminobiotin, desthiobiotin, biotin or no biotin 24 h before gene expression analyses. Transcriptional activities of genes encoding IL-2 and IL-2R were increased up to 43% in cells supplemented with diaminobiotin, desthiobiotin or biotin compared with biotin-deficient cells, as judged by luciferase activities after transfection with reporter-gene constructs. These findings are consistent with the hypothesis that diaminobiotin and desthiobiotin mimic the effects of biotin on gene expression and thus have biotin-like activities. Supplementation of cells with diaminobiotin and desthiobiotin did not affect abundances of holocarboxylases and activities of propionyl-CoA carboxylase, suggesting that effects of synthetic biotin metabolites on gene expression are not mediated by carboxylase-dependent pathways. It is not known whether naturally occurring biotin metabolites also have biotin-like activities.
KEY WORDS: • biotin metabolites • gene expression • humans • interleukin-2 • Jurkat cells
In mammals, biotin serves as a covalently bound coenzyme for four carboxylases: acetyl-CoA carboxylase (isoforms 
and ß; EC 6.4.1.2), pyruvate carboxylase (EC 6.4.1.1), propionyl-CoA carboxylase (PCC; EC 6.4.1.3) and 3-methylcrotonyl-CoA carboxylase (EC 6.4.1.4) (1
). These carboxylases catalyze essential steps in the metabolism of glucose, amino acids and fatty acids. Furthermore, human cells bind biotin to histones (DNA-binding proteins) in an enzyme-mediated reaction (2
,3
); biotinylation of histones might play a role in cell proliferation and DNA repair (3
,4
). Evidence is accumulating that expression of various genes depends on biotin (5
); the mechanism by which biotin exerts this effect is not known.
Two pathways of biotin catabolism have been identified in mammals and microorganisms: 1) ß-oxidation of the valeric acid side chain (6
–10
), leading to the formation of bisnorbiotin, tetranorbiotin and related metabolites that result from ß-oxidation of fatty acids (i.e., ,ß-dehydro-, ß-hydroxy and ß-keto-intermediates). 2) Sulfur oxidation in the heterocyclic ring, leading to the formation of biotin-l-sulfoxide, biotin-d-sulfoxide and biotin sulfone (6
,7
). Biotin metabolites are quantitatively important in mammalian tissues and body fluids; biotin metabolites account for 
50 to 70 mol/100 mol of the total biotinyl compounds (8
,9
,11
).
In classical nutrition studies, most biotin metabolites are considered metabolic waste with no known function. For example, metabolites with modifications in the ureido portion of the heterocyclic ring (e.g., the synthetic diaminobiotin) cannot participate in carboxylase reactions because the ureido portion plays an essential role in the carboxylation of organic acids (12
). Similarly, modifications in the valeric acid side chain of the biotin molecule (e.g., bisnormethylbiotin and tetranormethylbiotin) (8
,13
) render these metabolites inactive because they cannot undergo activation by binding of AMP, a prerequisite for binding to carboxylases (12
). In contrast, amino acid or peptide conjugates of biotin (e.g., biotinyl-
-lysine) have an intact valeric acid side chain and heterocyclic ring; free, bioactive biotin can be released from these metabolites (14
).
The present study tested the hypothesis that synthetic biotin metabolites such as diaminobiotin and desthiobiotin (Fig. 1
) can mimic the effects of biotin on gene expression. The following model was used to test this hypothesis. TH1 lymphocytes and some lymphoid cell lines (e.g., Jurkat cells) secrete interleukin-2 (IL-2) in response to stimulation by antigens (15
). After secretion into the extracellular space, IL-2 binds to IL-2 receptors (IL-2R), ß, and located on the surface of T and B cells, natural killer cells, some myeloid cells and cell lines such as Jurkat cells (15
,16
). Binding of IL-2 to receptors stimulates growth and differentiation of immune cells (15
–17
). Ultimately, IL-2/IL-2R complexes are endocytosed and degraded (18
–24
) to avoid excessive stimulation of the immune system by IL-2. Previous studies have suggested that expression of genes encoding IL-2 and IL-2R depends on biotin in Jurkat cells (25
). Biotin deficiency leads to a net increase in concentrations of extracellular IL-2 (despite decreased transcriptional activity of the IL-2 gene) due to decreased IL-2R–dependent endocytosis (25
). In the present study, we determined whether diaminobiotin and desthiobiotin enhance the expression of genes encoding IL-2 and IL-2R in biotin-deficient Jurkat cells, and whether effects of diaminobiotin and desthiobiotin are mediated by binding to biotin-dependent carboxylases. Theoretically, the effects of diaminobiotin and desthiobiotin on gene expression are consistent with the hypothesis that biotin metabolites have biotin-like activities.
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MATERIALS AND METHODS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Jurkat cells (clone E6–1) were purchased from American Type Culture Collection (Manassas, VA). Cells were cultured in customized (biotin-free) RPMI-1640, containing 0.1 L fetal bovine serum/L final medium, 100,000 IU/L penicillin and 100,000 µg/L streptomycin as described previously (26 ). Endogenous biotin was removed from fetal bovine serum by avidin chromatography; the absence of biotin from serum was confirmed by the avidin-binding assay (26 ). Culture media were replaced with fresh media every 48 h. Biotin and synthetic biotin metabolites were added to culture media to produce the treatment groups and time intervals described in Table 1. Previous studies have provided evidence that culturing Jurkat cells in biotin-deficient medium for 35 d provides sufficient time for cells to be depleted of biotin-dependent carboxylases (26 ).
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10 nmol/L biotin in healthy adults (29
); thus, this concentration represents a pharmacologic concentration of biotin in plasma. Fourth, culturing of Jurkat cells in medium containing 10 nmol/L of biotin significantly increases the expression of genes encoding IL-2 and IL-2R compared with cells cultured in medium containing 0.025 nmol/L (25
). Biotin impurities in stock solutions of diaminobiotin and desthiobiotin (Sigma, St. Louis, MO) were quantified using HPLC and the avidin-binding assay (30 ). Both diaminobiotin and desthiobiotin contained trace amounts of biotin, contributing an additional 0.01 nmol/L of biotin to the culture media described in Table 1. On the basis of evidence provided below, this amount is negligible compared with the 10 nmol/L of diaminobiotin or desthiobiotin in culture media.
PCC carboxylase activity.
This assay quantifies the binding rate of radioactive bicarbonate to propionyl-CoA, catalyzed by PCC in samples of lysed cells. PCC activity was quantified as described previously (31 ) with minor modifications (26 ). Briefly, lysed Jurkat cells were incubated with propionyl-CoA, [14C]bicarbonate and cofactors to allow for covalent binding of [14C]bicarbonate to propionyl-CoA. After incubation, unbound [14C]bicarbonate was volatilized by the addition of perchloric acid and samples were dried. Finally, samples were suspended in scintillation fluid and the bound [14C]bicarbonate was quantified by liquid scintillation counting.
Biotinylation of biotin-dependent carboxylases.
Holocarboxylases (as opposed to apocarboxylases) contain covalently bound biotin. Biotin in holocarboxylases was quantified by Western blot analysis, using streptavidin peroxidase as a probe for biotin as described in our previous studies (26
). Evidence exists that avidin and streptavidin also bind biotin metabolites such as desthiobiotin and diaminobiotin (32
–34
); thus, carboxylase-bound diaminobiotin and desthiobiotin can be probed with streptavidin if the binding of biotin metabolites to carboxylases occurs in cells. Note that the biotin-containing -chains of PCC and 3-methylcrotonyl-CoA carboxylases have similar molecular masses (80 and 83 kDa, respectively) and migrate as a single band; ß-chains of these two carboxylases are not biotinylated. Gel densitometry was used to confirm that equal amounts of protein were loaded per lane (26
).
Secretion of IL-2.
Secretion of IL-2 was induced by incubating 106 Jurkat cells with 50 µg/L of phorbol-12-myristate-13-acetate (PMA) and 2 mg/L of phytohemagglutinin (PHA) for 6 h in a final volume of 260 µL as described previously (26 ). The cell-free media supernatant was collected by centrifugation (4,500 x g for 2 min) and analyzed for IL-2 by using a commercial ELISA (hIL-2 ELISA, Biosource, Camarillo, CA) as described previously (26 ).
Reporter-gene constructs.
The following constructs were used to model the effects of biotin and synthetic metabolites on the 5'-flanking regions of genes encoding IL-2 and IL-2R. 1) A construct of the regulatory region of the IL-2 gene (spanning 321 bases upstream of the transcription start site) linked to the luciferase gene [denoted "p(-321)IL2-Luc"] was provided by L. P. Freedman (Memorial Sloan-Kettering Cancer Center, New York, NY) (35
). The regulatory elements of the IL-2 gene are located within 300 bases upstream of the transcription start site (36
,37
). 2) A construct of the regulatory region of the IL-2R gene (spanning 600 bases upstream of the transcription start site) linked to the luciferase gene (denoted "pPB600") was provided by H. Asao (Tohoku University School of Medicine, Sendai, Japan) (38
). The regulatory elements of the IL-2R gene are located within 600 bases upstream of the start site (38
). 3) A construct of the Rous sarcoma virus (RSV) promoter linked to the ß-galactosidase gene (denoted "RSV ßgal") was used as control for transfection efficiency (provided by B. R. White, University of Nebraska-Lincoln).
Fifteen million cells were cotransfected with luciferase constructs [p(-321)IL2-Luc or pPB600] and control (RSV ßgal) by using SuperFect (Qiagen, Valencia, CA) according to the manufacturer’s instructions. Twenty-four hours after transfection, cells were stimulated with 50 µg/L PMA and 2 mg/L PHA for 6 h to induce expression of reporter genes. Luciferase activity was assayed by LucLite Plus (Packard, Boston, MA) according to the manufacturer’s instructions, using a Top Count NXT (Packard). ß-Galactosidase activity was assayed using a commercial assay kit (Promega, Madison, WI) and an Emax Microwell Plate Reader (Molecular Devices, Sunnyvale, CA). Luciferase activities were normalized for transfection efficiency, as judged by ß-galactosidase activity in response to transfection with RSV ß-gal.
Statistics.
Homogeneity of variances among groups was tested using Bartlett’s test (39 ). When variances were heterogeneous, data were log-transformed before further statistical testing. The ignificance of differences among groups was tested by one-way ANOVA. Fisher’s Protected Least Significant Difference procedure was used for post-hoc testing (39 ). StatView 5.0.1 (SAS Institute, Cary, NC) was used to perform all calculations. Differences were considered significant when P < 0.05. Data are expressed as means ± SD.
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RESULTS |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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Biotinylation of carboxylases (abundance of holo-carboxylases) in Jurkat cells correlated with biotin supply in culture media. Biotinylated pyruvate carboxylase, PCC and 3-methylcrotonyl-CoA carboxylase were not detectable by visual inspection of Western blots, generated by using extracts of cells cultured in biotin-deficient, diaminobiotin and desthiobiotin media (Fig. 2A
). In contrast, holocarboxylases were detectable in biotin-replenished cells and in controls. Note that the biotin-containing -chains of PCC (molecular mass = 80 kDa) and 3-methylcrotonyl-CoA carboxylase (molecular mass = 83 kDa) migrate as one single band on the polyacrylamide gels used here. Acetyl-CoA carboxylase was not detectable in any of the treatment groups, consistent with previous studies in Jurkat cells (26
).
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Taken together, these findings are consistent with the hypotheses that biotin concentrations in culture media affected intracellular biotin concentrations, as judged by biotin-dependent carboxylases, and that biotin impurities (<0.01 nmol/L) in preparations of diaminobiotin and desthiobiotin (10 nmol/L; see Materials and Methods) did not affect biotinylation of carboxylases.
Secretion of interleukin-2.
Binding of IL-2 to IL-2 receptors triggers both signal transduction cascades, leading to cellular growth and differentiation (15
), and endocytosis of IL-2 and its receptors, leading to intracellular degradation of these proteins (18
–24
). Previous studies suggested that expression of the gene encoding IL-2R depends on biotin; decreased expression of IL-2R in biotin-deficient cells leads to decreased endocytosis of IL-2 and thus increased concentrations of IL-2 in the extracellular medium (25
).
Here we determined whether IL-2 accumulates in biotin-deficient culture medium compared with controls and whether supplementation of biotin-deficient medium with diaminobiotin, desthiobiotin or biotin prevents extracellular accumulation of IL-2; we also investigated the time course of extracellular concentrations of IL-2 in response to supplementation with biotin and synthetic biotin metabolites. Cells were cultured in media described in Table 1; diaminobiotin, desthiobiotin, or biotin were added to media 2–48 h before cells were stimulated with PMA and PHA to induce synthesis of IL-2.
When cells were cultured in biotin-deficient medium for 35 d and stimulated with PMA and PHA for 6 h, the extracellular concentration of IL-2 was 120 ± 8.5% of control values (Fig. 3A ). Supplementation of biotin-deficient cells with biotin for 2–48 h decreased concentrations of extracellular IL-2 to levels observed in controls. Supplementation of biotin-deficient cells with diaminobiotin or desthiobiotin for 2–48 h also decreased concentrations of extracellular IL-2 to levels observed in controls (Figs. 3 B and C). These findings are consistent with the hypothesis that synthetic biotin metabolites can mimic the effects of biotin on the secretion of IL-2. Effects of biotin and biotin metabolites on secretion of IL-2 occurred rapidly, i.e., within 2 h after supplementation of culture media (Figs. 3 A–C).
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gene.
Biotin and biotin metabolites affected the expression of the gene encoding IL-2R, as determined in cells transfected with reporter-gene constructs. When cells were cultured in biotin-deficient medium for 35 d, luciferase activities in pPB600-transfected cells decreased to 25 ± 6.7% of control values (Fig. 4
). When biotin-deficient cells were supplemented with 10 nmol/L biotin at the time of transfection with pPB600 (i.e., 24 h before stimulation with PMA and PHA), luciferase activities increased to 49 ± 17% of control values. Similarly, when biotin-deficient cells were supplemented with 10 nmol/L of diaminobiotin or desthiobiotin, luciferase activities increased to 68 ± 18 and 44 ± 12%, respectively, of control values. These findings are consistent with the hypothesis that synthetic biotin metabolites can mimic the effects of biotin on gene expression.
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Expression of the IL-2 gene.
When cells were cultured in biotin-deficient medium for 35 d, luciferase activities in p(-321)IL2-Luc-transfected cells decreased to 21 ± 1.7% of control values (Fig. 5 ). When biotin-deficient cells were supplemented with 10 nmol/L of biotin at the time of transfection with p(-321)IL2-Luc (i.e., 24 h before stimulation with PMA and PHA), luciferase activities increased to 31 ± 2.2% of control values. Similarly, when biotin-deficient cells were supplemented with 10 nmol/L of diaminobiotin or desthiobiotin, luciferase activities increased to 33 ± 0.2 and 38 ± 0.7%, respectively, of control values. These findings are consistent with the hypothesis that synthetic biotin metabolites can mimic the effects of biotin on gene expression. In spite of the increased expression of the IL-2 gene in biotin-supplemented cells, the apparent secretion of IL-2 into the culture media is lower in biotin-supplemented cells compared with biotin-deficient cells (Figs. 3 A–C) due to increased endocytosis of IL-2 in supplemented cells (25 ).
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DISCUSSION |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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. Effects of these synthetic biotin metabolites on gene expression are likely to be independent of biotinylation of carboxylases, based on the following lines of evidence. Supplementation of biotin-deficient cells with diaminobiotin and desthiobiotin mediated increased transcriptional activity of genes encoding IL-2 and IL-2R despite unchanged PCC activities; in contrast, supplementation of biotin-deficient cells with biotin increased both gene expression and PCC activity. By which mechanism might biotin and its metabolites affect gene expression? Recently, Solorzano-Vargas et al. (40 ) proposed that an intermediate of biotin metabolism, biotinyl-AMP, activates soluble guanylate cyclase, leading to increased production of cGMP. cGMP stimulates protein kinase G, leading to phosphorylation of the proteins that regulate transcription.
Biotinyl-AMP is an intermediate in the synthesis of holocarboxylases; formation of biotinyl-AMP is catalyzed by holocarboxylase synthetase (10 ). In the present study, biotinylation of carboxylases was not affected by diaminobiotin and desthiobiotin. However, this does not exclude the possibility that holocarboxylase synthetase might have produced diaminobiotinyl-AMP and desthiobiotinyl-AMP without ligating the diaminobiotinyl and desthiobiotinyl residues to carboxylases. In future studies, the use of biotin metabolites that cannot be converted to AMP derivatives (e.g., biotinol) might provide insights into the regulation of gene expression by biotin metabolites.
Theoretically, most of the known mammalian biotin metabolites are potential targets for conjugation to AMP; thus, they might have biotin-like activities. For example, biotin sulfoxides, biotin sulfone and bisnorbiotin have a carboxyl group in their side chain (10 ), a prerequisite for conjugation to AMP. Also, these biotin metabolites are among the quantitatively most important biotinyl compounds in mammalian tissues (8 ,9 ,11 ). Some biotin metabolites (biotinylated peptides such as biocytin) can be hydrolyzed to release free biotin (14 ), providing substrate for conjugation to AMP. Only a few of the known biotin metabolites (e.g., bisnorbiotin methyl ketone) do not have a carboxylic acid side chain (9 ) and thus are not potential targets for conjugation to AMP; these metabolites cannot affect gene expression by the mechanism proposed by Solorzano-Vargas et al. (40 ).
In an alternative model, we (3
) and the research group that originally documented the biotinylation of histones by biotinidase (2
) have hypothesized that gene expression is affected by the binding of biotin to histones. Although biotinylation of histones may have a possible role in gene expression, diaminobiotinylation and desthiobiotinylation of histones are mechanisms that are unlikely to affect transcriptional activities of genes, for the following reasons: 1) biotinylation of histones depends on biocytin (biotinyl--lysine) as donor of the biotinyl moiety (2
); 2) biocytin is produced during degradation of biotinylated carboxylases (14
); 3) the present study has provided evidence that diaminobiotin and desthiobiotin do not bind to carboxylases; thus, no diaminobiotinyl--lysine or desthiobiotinyl--lysine are produced during degradation of carboxylases, rendering diaminobiotinylation and desthiobiotinylation of histones unlikely.
Effects of diaminobiotin, desthiobiotin, and biotin on gene expression occurred rapidly (within 2 h) after supplementation of culture media with these compounds. Note, however, that cells were incubated with PMA and PHA for 6 h after supplementation with biotin and synthetic biotin metabolites to stimulate expression of the genes under investigation. Thus, the total time of exposure to biotin and metabolites (2–48 h of biotin and metabolites plus 6 h of PMA and PHA) is sufficient to permit synthesis of new proteins such as IL-2 and IL-2R.
Is it possible that biotin impurities in preparations of diaminobiotin and desthiobiotin mediated effects on gene expression? The following lines of evidence suggest that this is an unlikely scenario: 1) Biotin impurities were quantitatively minor in the preparations of commercial biotin metabolites used here (0.01 nmol/L of biotin/10 nmol/L of biotin metabolites). 2) Supplementation of biotin-deficient cells with biotin metabolites did not affect biotinylation of carboxylases. 3) Biotin metabolites compete successfully with biotin for cellular transport (41
); transport discrimination to favor uptake of biotin over biotin metabolites is likely to be quantitatively modest compared with the quantitative effects of the large differences in the concentrations of biotin and biotin metabolites in our experiments. 4) Most importantly, supplementation of biotin-deficient medium (0.025 nmol/L) with biotin at the same levels (0.01 nmol/L) as those in diaminobiotin medium and desthiobiotin medium did not affect transcriptional activity of genes encoding IL-2 and IL-2R to the same extent as observed for cells supplemented with diaminobiotin and desthiobiotin.
The present study provided evidence that synthetic biotin metabolites have biotin-like activities because they mimic the effects of biotin on gene expression. It is not known whether naturally occurring biotin metabolites also have biotin-like activities. Exploring biotin-like activities of naturally occurring biotin metabolites appears to be a worthwhile endeavor, given that >50% of the biotinyl compounds in tissues and body fluids are biotin metabolites (8 ,9 ,11 ).
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ACKNOWLEDGMENTS |
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FOOTNOTES |
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3 Abbreviations used: IL-2, interleukin-2; IL-2R, interleukin-2 receptor ; PCC, propionyl-CoA carboxylase; PHA, phytohemagglutinin; PMA, phorbol-12-myristate-13-acetate; RSV, Rous sarcoma virus.
Manuscript received 3 December 2002. Initial review completed 9 January 2003. Revision accepted 16 January 2003.
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LITERATURE CITED |
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TOPABSTRACTMATERIALS AND METHODSRESULTSDISCUSSIONLITERATURE CITED |
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