Biotin deficiencies, metabolic

M3. Macleod, P. R., and Lardy, H. A., Metabolic functions of biotin. II. The fixation of carbon dioxide by normal and biotin deficient rats. J. Biol. Chem. 179, 733-741 (1949). 

Fig. 5 Metabolic blocks caused by biotin deficiencies. There are a small number of proteins that are biotinylated in vivo. Note that the naturally occurring biotin and biotinylated proteins may interfere with applications that use strept(avidin) on biological samples...

Biotin deficiency and the functional deficiency associated with lack of holo-carboxylase synthetase (Section 11.2.2.1), or biotinidase (Section 11.2.3.1), causes alopecia (hair loss) and a scaly erythematous dermatitis, especially around the body orifices. The dermatitis is similar to that seen in zinc and essential fatty acid deficiency and is commonly associated with Candida albicans infection. Histology of the skin shows an absence of sebaceous glands and atrophy of the hair follicles. The dermatitis is because of impaired metabolism of polyunsaturated fatty acids as a result of low activity of acetyl CoA carboxylase (Section 11.2.1.1). In biotin-deficient experimental animals, provision of supplements of long-chain 6 polyunsaturated fatty acids prevents the development of skin lesions (Mock et al., 1988a, 1988b Mock, 1991). 

Cot Death Cot death, or Sudden Infant Death Syndrome, when an apparently healthy child dies suddenly, and from no apparent cause, has some similarities with the fatty liver and kidney syndrome in birds. It has been suggested that it may result from marginal biotin deficiency, together with a precipitating metabolic stress. 

Mock DM, Baswell DL, Baker ff, ffolman RT, and Sweetman L (1985) Biotin deficiency complicating parenteral alimentation diagnosis, metabolic repercussions, and treatment.of Pediatrics 106, 762-9. 

Biotin deficiency results from a number of inborn errors of metabolism, and biotin quantitation therefore represents a general screening method for these diseases. Recently, a new method was proposed for biotin quantitation in serum. The method has been called an ELLSA, and relies on the following competitive reaction ... 

It influences fat metabolism, decarboxylation and carbon dioxide fixation, and deamination of some amino acids. It is closely related metabolically to pantothenic acid and folic acid. A biotin deficiency may be induced by ingestion of avidin, a raw-egg protein, because of the formation of a nonabsorbable biotin-avidin complex. Biotin is synthesized in the intestinal tract of humans therefore, normally it is not essential in the diet. 

The metabolic action of biotin is mediated through biotin-dependent enzymes that actively synthesize purines. It is a stable monocarboxylic acid, soluble in water and alcohol, and acts as a coenzyme as well as a growth factor, even in very small quantities. Biotin deficiencies cause scaly dermatitis, hyperkeratosis and alopecia. Topical application of biotin reduces the secretion of sebum. 

Seborrheic Dermatitis and Biotin Deficiency 278 Biotin Deficiency The Role of Biotin in Metabolism... 

All aspects of the biochemical role of biotin have not yet been clarified. The vitamin has been implicated in the metabolism of carbohydrates, lipids, proteins, and nucleic acids. Available evidence indicates that biotin acts as a CO2 carrier in a number of carboxyla-tion and decarboxylation reactions connected with carbohydrate and fatty acid metabolism. A number of experimental procedures are used to establish the participation of biotin in a given biochemical reaction (1) the study of enzyme activity in biotin-deficient animals (2) the effect of avidin administered in vivo or added to the incubation mixture on the activity of the enzyme under study and (3) purification of the enzyme and demonstration of the existence of enzyme-bound biotin. Studies of this kind have established that biotin is required for the carboxylases of jS-methyl-crotonyl CoA, acetyl-CoA, propionyl CoA, and oxaloacetic transcarboxylase. Only some of the results are presented here [74-76]. 

The metabolic pathway for propionic acid use in mammals involves the carboxylation of propionyl CoA in the presence of a specific carboxylase and ATP. The products of the reaction are methylmalonyl CoA and ADP. The ultimate product of propionate metabolism is succinate, which is oxidized via the Krebs cycle. These reactions all occur in the mitochondria. The ability of the mitochondria of biotin-deficient animals to use propionic acid is reduced. This metabolic defect of the deficient mitochondria cannot be corrected by adding biotin in vitro, but the rate of propionic acid use by mitochondria is restored to normal if the deficient animals are fed a normal diet containing biotin. 

Prior to 1981, human biotin deficiency had been reported only in children with inborn errors of intermediary metabolism or in individuals ingesting excessive intakes of raw egg white or experimental diets which excluded biotin (Tanaka, 1981). Since then, there have been several case reports of TPN-associated biotin deficiency (Mock et al, 1981 Kien et al, 1981 Gillis et al., 1982). The children in these reports all suffered from gastrointestinal abnormalities and had received biotin-free, or deficient, parenteral formulations for extended time periods with little or no oral intake. It appears that patients with altered intestinal flora secondary to antibiotic treatment, diminished gut motility, or abnormal intestinal anatomy, are at risk of deficiency on long-term biotin-free TPN. 

Biotin carboxylases and relationship with intermediate metabolism. Alternative pathways responsible of organic acids accumulation (dashed arrows) take place with deficient carboxylases (black bars) as a consequence of biotin deficiency. ACCl and ACC2 acetyl-CoA carboxylase 1 and acetyl-CoA carboxylase 2 PC pyruvate carboxylase PCC pro-pionyl CoA carboxylase MCC methylcrotonyl CoA carboxylase. 

Biotin deficiency may be caused by inborn errors on other proteins involved in biotin homeostasis biotidinase, the sodium-dependent multivitamin transporter and holocarboxylase synthetase (Zempleni et al. 2008). A congenital deficiency of either of these proteins may create impairments in essential metabolisms, causing clinical signs with various intensities. 

Reduced activities of carboxylase enzymes can cause a metabolic block of certain substrates and a use of alternative pathways for catabolism. Therefore, 3-hydroxyisovaleric acid and 3-methylcrotonyl glycine are formed consequently to a shunt of 3-methylcrotonyl carboxylase counterbalancing its activity decrease. Marginal biotin deficiency experimentally induced by 20 days of free biotin diets in human increased 3-hydroxyisovaleric acid excretion in urine above the upper limit of normal. The normal urinary excretion of 3-hydroxyisovaleric acid in healthy adults is 112 38 pmol per 24 hours (Mock et al. 1997). This suggests that 3-hydroxyisovaleric acid urinary excretion is a good indicator of marginal biotin deficiency. 

Biotin deficiency causes disturbances in a variety of carboxylase-mediated metabolic reactions. As a result, such a deficiency may induce ketolactic acidosis and organic aciduria (Zempleni et al. 2008). Organic acids such as 3-methylcrotonylglycine, 3-hydroxyvaleric acid or methylcitric acid are excreted in urine in case of biotin deficiency (Figure 43.2). 

Watanabe, Y., Ohya, T., Ohira, T., Okada, J., Fukui, T., Watanabe, T., Inokuchi, T., Yoshino M., and Matsuishi, T., 2010. Secondary biotin deficiency observed in two Japanese infants due to chronic use of hypoallergic infant formula. Journal of Inherited Metabolic Disease. 33(Suppl 1) SI69 549-P. 

Another of the water-soluble B vitamins known to have a function for some bacteria and animals is biotin. A role in carbohydrate metabolism has been suggested. A protein substance called avidin, when fed in the form of large amounts of raw egg yolk, combines with biotin, and may thus cause a biotin deficiency in some species. Somewhat similar symptoms have been reported in human subjects (Sydenstricker et al., 1942). Intestinal synthesis and the antivitamin may explain the failure to confirm this observation. No definite requirement for the diet can be stated. 

This review is dedicated to Michel Gaudry (1942-1998), who contributed to many aspects in the research field of biotin biochemistry (biotin metabolism, biotin transport, biotin deficiency, and so on). His outstanding contribution to the previous editions of this book chapter is gratefully acknowledged. 

Biotin Dependency. A rare inherited disease called biotin dependency is known. In people with the disease, the body s use of biotin, the B vitamin necessary for certain metabolic processes, is somehow disrupted. Symptoms include loss of hair, lethargy, coma, and susceptibility to infections. The only treatment is daily doses of biotin. In 1981, medical researchers at the University of California in San Francisco reported successfully (1) diagnosing a biotin deficiency of an unborn baby by examining the amniotic fluid (the fluid was extracted from the womb by a procedure called amniocentesis, then cells from the fluid were grown in various nutrients and compared with normal cells) and (2) giving the mother massive doses of biotin, enough of which passed through the placenta so that the baby was born healthy. 

This vitamin was discovered by Kdgl in 1934 and later identified with Gydi s vitamin P M5). The protein-bound form of this vitamin can be liberated by a peptidase lJi6). The metabolic events which appeared defective in biotin deficiency are associated with the fixation of COt in various biosynthetic processe6 H7-149). A more specific chemical participation of botin in CO fixation was formulated recently by L3men ef al. ISO) who studied the mechanism of the enzymic carboxylation of fj-hydroxyisovaleryl CoA. The over-all process is as follows ... 

Daily doses up to 200 mg orally and up to 20 mg intravenously have been given to treat biotin-responsive inborn errors of metabolism and acquired biotin deficiency. Toxicity has not been reported. 

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