Deficiency, biochemical biotin

The problem is a functional deficiency of biotin, due both to inability to re-letise free biotin from dietary hiocytin tmd cdso to failure of the normal recovery of free biotin by biotinidase action on the hiocytin released by proteolysis of biotin-containing enzymes. Normal intcikes of biotin are inadequate to meet the requirements of these patients the provision of pharmacological doses of free biotin provides an adequate cunount to meet requirements without the need for reutilization. The delayed development of clinical and biochemical abnormalities is a result of the accumulation of biotin by the fetus, so that at birth the infant has adequate stores of the vitamin. 

Two children with the late-onset form initially were reported as having a defect in intestinal transport of biotin. This conclusion was supported by finding low plasma biotin concentrations when these children were administered oral biotin compared to the concentrations of plasma biotin of unaffected control subject. In 1983, it was demonstrated that the primary biochemical defect in most patients with late-onset multiple carboxylase deficiency was a deficiency of serum biotinidase activity. The two children with a putative defect in intestinal biotin transport both were confirmed to have biotinidase deficiency. This disparity was reconciled by demonstrating that, in both cases, the children were biotin depleted at the time the biotin-loading studies were performed. Therefore, when the children initially were given biotin, although the vitamin was transported into the blood normally, it was rapidly taken up... 

If the child with profound biotinidase deficiency is symptomatic, then the biochemical abnormalities and seizures resolve rapidly after biotin treatment. This is usually followed by improvement of the cutaneous abnormalities. Hair growth returns over a period of weeks to months in the children with alopecia. Optic atrophy and hearing loss are usually resistant to therapy, especially if several months have elapsed between the time of diagnosis and the initiation of treatment. Some treated children have rapidly regained lost developmental milestones, whereas others have continued to show deficits. 

Biotin deficiency in animals results in alopecia, a. scaly dermatitis, anorexia, and eventually death. Some of the biochemical changes occurring in rats consuming a biotin-deficient diet containing raw egg white are illustrated in Figure 9.33. The animals consumed the diet for up to 30 days. The activities of three biotin-requiring enzymes were determined in the livers of rats killed at the indicated times. The en iymes measured were acetyl-CoA carboxylase ( , propionyl-Co A carboxylase (O), and pyruvate carboxylase (A). 

FIGURE 9.33 Biochemical changes occurring in rats consuming a biotin-deficient diet containing raw egg white, iRedrawn with permission from Arin e and Mistry, 1971.)... 

Arinze, J. C., and Mistry, S. P (1971). Activities of some biotin enzymes and certain aspects of gluconeogenesis during biotin deficiency. Comp. Biochem. PJjysEoL B 38,285-294. 

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]. 

Biotin, once a mysterious compound needed to breed healthy rats, is now known to participate in a vital biochemical reaction. In spite of this striking progress in the molecular biology of biotin, the pathogenesis of the seborrheic dermatitis of biotin-deficient children remains unexplained. The molecular pathologist must link the dermatitis with biotin s role in the carboxylation reaction. 

Biotin deficiency implies biochemical and clinical disturbances of mammals vital functions. 

DAKSHINAMURTI, K., CHEAH-TAN, C. (1968b) Liver glucokinase of the biotin deficient rat. Can. J. Biochem., 46, 75-80. 

GRIFFIN, J. B., ZEMPLENI, J. (2005) Biotin deficiency stimulates survival pathways in human lymphoma cells exposed to antineoplastic drugs. J. Nutr. Biochem., 16, 96-103. 

Hydroxy- 9-methylglutaryl CoA further yields acetyl CoA and acetoacetic acid, as was shown earlier by Coon et cU. (I48). In biotin deficiency the carboxylation reaction does not occur. It was shown by Lynen et al. that the actual carboxylation is preceded by the enzymic dehydration (rf jS-hydroxyisovaleryl CoA to /8-methylcrotonyl CoA, which is the true substrate for the entry of CO2. TTiis occurs at the expense of the hydrolysis of the terminal P04 of ATP. The unsaturated intermediate is then saturated by the addition of H2O to yield the final product. The critical step of this carboxylation is the conversion of CO2 to a reactive form. The analogy of the biochemical activation of other substances through an acyl adenylate type of compound did not fit CO2 activation. The final mechanism of the activation of CO2 was derived from the discovery that the carboxylase enzyme was a biotin-protein. This observation explains earlier work 149) which indicated that biotin is a cofactor of the fatty acid-synthesizing enzyme system. When the purified carboxylase was incubated with P and ATP an exchange reaction of phosphate occurred, which was inhibited by avidin, a protein which specifically binds biotin. This indicated that the primary reaction in CO2 fixation is the combination of ATP with the biotin-protein enzyme to yield ADP biotin-protein -f P. The active CO2 is then the product of an exchange reaction between ADP and C02 which is finally attached to the biotin-protein complex. 

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