Biotin Deficiency In Pregnancy

Biotin deficiency in experimental animals is teratogenic, and a number of the resultant birth defects resemble human birth defects. Up to half of pregnant women have elevated excretion of 3-hydroxy-isovaleric acid (Section 11.4), which responds to supplements of biotin, in the first trimester, suggesting that marginal status may be common in early pregnancy and may be a factor in the etiology of some birth defects. This may be the result of increased catabolism of biotin as a result of steroid induction of biotin catabolic enzymes; there is increased excretion of bisnorbiotin and biotin sulfoxide (Zempleni and Mock, 2000a; Mock et al., 2002).


The plasma concentration of the biotin does not provide a sensitive index of status, at least partly because there is increased renal reabsorption of the vitamin as intake falls. Urinary excretion of biotin and its metabolites is more sensitive, but may be confounded by changes in biotin excretion caused by glucocorticoid hormones (McMahon, 2002). There are three sensitive markers of status (Mock, 1999):

1. The activity of propionyl CoA carboxylase in lymphocytes falls, and the activation of the apoenzyme on incubation with biotin rises, in patients receiving total parenteral nutrition before there is any change in the plasma concentration of biotin (Velazquez et al., 1990). In experimental animals, the activity of lymphocyte propionyl CoA carboxylase falls early during biotin depletion, at the same time as the activity of the hepatic enzyme. There is not the expected increase in urinary excretion of hydroxypropionic acid, presumably because propionyl CoA carboxylase is not rate-limiting for propionate metabolism (Mock and Mock, 2002).

2. Reduced activity of methylcrotonyl CoA carboxylase (Section results in the formation and excretion of 3-hydroxy-isovaleric acid; in experimental biotin depletion, significant amounts of 3-hydroxy-isovaleric acid are excreted at the same time as the excretion of biotin and bisnor-biotin falls, before there is any change in the plasma concentration of biotin (Mock et al., 1997).

3. As a result of impaired activity of acetyl CoA and propionyl CoA carboxylases, there are changes in the fatty acid composition of lipids in the lymphocytes of biotin-deficient rats. There is an increase in the proportion of long-chain fatty acids (C22:0 to C30:0) and odd-carbon fatty acids (C15:0 to C29:0), with a decrease in the proportion of unsaturated fatty acids and the ratio of ds-vaccenic acid (C18:1&>9): palmitoleic acid (C16:1&>6), which is indicative of impaired elongation and desaturation of fatty acids (Liu et al., 1994).


It is apparent from the discussion in Section 11.3 that there is little information concerning human biotin requirements and no evidence on which to base recommendations. Average intakes of biotin range between 15 to 70 [g per day. Such intakes are obviously adequate to prevent deficiency, and the safe and adequate range of biotin intakes is set at 10 to 200 [g per day (Department of Health, 1991; Scientific Committee for Food, 1993). The U.S./Canadian adequate intake for adults is 30 [g per day (Institute of Medicine, 1998).

On the basis of studies in patients who developed deficiency during total parenteral nutrition, and who are therefore presumably wholly reliant on an exogenous source of the vitamin - with no significant contribution from intestinal bacterial synthesis - the provision of 60 [g of biotin per day for adults receiving total parenteral nutrition is generally recommended (Bitsch et al., 1985).

1 1.6 AVIDIN

The original interest in avidin was because of the egg white injury that was subsequently shown to be avidin-induced biotin deficiency. Thereafter, avidin was used because of its high affinity for biotin (a dissociation constant of 10-15 molper L), not only to induce experimental biotin deficiency, but also to bind to biotin in isolated enzymes and thus, by irreversible inhibition, demonstrate the coenzyme role of biotin. Because of the stability of the avidin-biotin complex, it has not been possible to use immobilized avidin as a means of purifying biotin enzymes - there seems to be no way in which the enzyme can be released from avidin binding. Because of its high affinity for biotin, avidin is used to provide an extremely sensitive system for linking reporter molecules in a variety of analytical systems.

Avidin has been found in the eggs and oviducts of many species of birds and in the egg jelly of frogs, but not in other tissues and not in the mammalian oviduct. It accounts for 0.05% of the total proteins of egg white. Avidin is synthesized in the goblet cells of the epithelium of the oviduct, whereas the other egg white proteins are synthesized in the underlying tubular gland cells. Its synthesis is induced by progesterone.

Avidin is a strongly basic glycoprotein; 10% of the molecular weight is carbohydrate - mannose and N-acetyl glucosamine linked to asparagine, with a high degree of heterogeneity in the sequence of the carbohydrate residues. These carbohydrate residues are not essential for biotin binding. Commercially available avidin consists of a mixture of glycosylated and unglycosylated forms that can be separated electrophoretically or on concanavalin A columns, but that cannot be distinguished on the basis of their biotin binding.

A closely similar protein, streptavidin, has been isolated from culture filtrates of several species of Streptomyces. Unlike avidin, streptavidin is not glycosylated and has an acidic isoelectric point. It binds biotin with a similarly high affinity.

Avidin is a tetrameric protein and binds 4 mol of biotin per tetramer; it also binds N-carboxybiotin with a somewhat lower affinity. The unit of avidin activity is that amount which will bind 1 pg (4.09 nmol) of biotin; commercially available avidin has an activity of 10 to 15 units per mg of protein.

The carboxyl group of the side chain of biotin is not essential for binding, and enzyme-bound biocytin will also bind to avidin. Binding is by hydrogen bonding to a hydrophobic pocket formed by two tryptophan residues at positions 70 and 110 in the peptide sequence. Adjacent to each of these tryptophan residues is a lysine that is also essential for biotin binding; there are similar conserved tryptophan-lysine sequences in streptavidin (Gitlin et al., 1988a, 1988b).

The physiological role of avidin in egg white is unknown. It is unlikely to act as a storage form of biotin, because most of the biotin of eggs is in the yolk, not the white, and most avidin occurs as the free glycoprotein, without biotin. Furthermore, biotin bound to avidin in egg white is not available to the developing chick embryo. Egg white contains 3 to 10 times more avidin than would be required to complex all the biotin in the yolk; feeding experimental animals on diets based on whole dried egg results in the development of biotin deficiency signs, despite the high biotin content of the yolk (White et al., 1992).

In Streptomyces, it is assumed that streptavidin has an antibiotic role; it is secreted together with a low molecular weight inhibitor of biotin synthesis, stra-vidin. It has been suggested that avidin in eggs has a similar role, to protect the developing embryo from (biotin-requiring) bacteria that penetrate the shell. Alternatively, because cells in culture can take up and utilize avidin-biotin, it has been suggested that the physiological role of avidin may be to facilitate the uptake of biotin by the developing embryo (Board and Fuller, 1974; Dakshinamurti et al., 1985; Bush and White, 1989).

Both avidin and the avidin-biotin complex are very stable to heat. To release biotin from avidin binding, autoclavingabove 130°Cisrequired, andfree avidin is stable up to about 85°C. Avidin is also resistant to proteolysis and, as is obvious from the use of raw egg white diets to induce biotin deficiency, biotin cannot be released from avidin binding in the gastrointestinal tract. Lysosomal hydrolases do release biotin from avidin binding, and intravenously administered avidin-biotin can be a source of biotin.

Because the side chain carboxyl group of biotin is not required for avidin binding, avidin will recognize and bind biotin esterified to proteins and other molecules. This is the basis of a variety of highly sensitive analytical systems (Airenne et al., 1999). Biotin can be attached to antibodies and other ligand binding proteins, group-specific reagents to permit detection of amino acids in proteins, carbohydrates, or functional groups in DNA and RNA. This creates a biotinylated probe, with each biotin residue binding to avidin. The avidin can be labeled with a colored, fluorescent, chemiluminescent, or electron-dense group, thus permitting ready detection, or the avidin may be linked to an enzyme as a reporter molecule, thus permitting further amplification. An alternative approach is to react the avidin-biotinylated probe complex with a biotinylated reported molecule that binds to the free sites of the avidin tetramer. Such assay systems have sensitivity equal to, or better than, conventional radioligand binding assays. The carbohydrate groups of avidin result in some nonspecific binding, thus giving an undesirably high background in some systems. The high isoelectric point of avidin also causes problems with some systems. Both of the problems are overcome if bacterial streptavidin is used rather than egg white avidin, and a number of genetically modified variants of streptavidin that have been designed for specific functions are available (Sano et al., 1998; Stayton et al., 1999).


Baumgartner ER and Suormala T (1997) Multiple carboxylase deficiency: inherited and acquired disorders of biotin metabolism. International Journal of Vitamin and Nutrition Research 67, 377-84. Baumgartner ER and Suormala T (1999) Inherited defects of biotin metabolism. Biofac-tors 10, 287-90.

Dakshinamurti K and Chauhan J (1988) Regulation of biotin enzymes. Annual Reviews of Nutrition 8,211-33.

Dakshinamurti K and Chauhan J (1989) Biotin. Vitamins and Hormones 45,337-84.

Dakshinamurti K and Chauhan J (1994) Biotin-binding proteins. In Vitamin Receptors: Vitamins asLigands in Cell Communication, K Dakshinamurti (ed.), pp. 200-49. Cambridge, UK: Cambridge University Press.

Hommes FA (1986) Biotin. World Review of Nutrition and Dietetics 48, 34-84.

Hymes J and Wolf B (1996) Biotinidase and its roles in biotin metabolism. Clinica Chimica Acta 255, 1-11.

Knowles JR (1989) The mechanism of biotin-dependent enzymes. Annual Reviews of Biochemistry 58, 195-221.

McMahon RJ (2002) Biotin in metabolism and molecular biology. Annual Reviews of Nutrition 22, 221-39.

Roth KS (1981) Biotin in clinical medicine - a review. American Journal of Clinical Nutrition 34, 1967-74.

Various authors (1999) Symposium proceedings: nutrition, biochemistry and molecular biology of biotin. Journal of Nutrition 129, 476s-503s.

Wolf B and Heard GS (1991) Biotinidase deficiency. Advances in Pediatrics 38,1-21.

Zempleni J and Mock D (2001) Biotin homeostasis during the cell cycle. Nutrition Research Reviews 14, 45-63.

References cited in the text are listed in the Bibliography.

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