Biotin Metabolism in H. sapiens
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Biotin Metabolism in H. sapiens

Biotin or Vitamin-H, an essential micronutrient for all mammals belongs to the B-Complex group of Vitamins. It is a water-soluble Vitamin used as co-factor of Biotin-dependent Carboxylases. The role of Biotin in Carboxylases is to act as vector for carboxyl-group transfer between donor and acceptor molecules during Carboxylation reaction (Ref.1). In H. sapiens (Homo sapiens), Biotin is a covalently bound as a prosthetic group for five Biotin-dependent Carboxylases namely PCC (Propionyl-CoA Carboxylase) group; PC (Pyruvate Carboxylase, Mitochondrial); MCC (Methylcrotonyl-Coenzyme-A Carboxylase) group; ACAC-Alpha (Acetyl-Coenzyme-A Carboxylase-Alpha) and ACAC-Beta (Acetyl-Coenzyme-A Carboxylase-Beta). Biotin is covalently attached to Carboxylases by the enzyme HLCS (Holocarboxylase Synthetase (Biotin-(Proprionyl-Coenzyme-A Carboxylase (ATP-Hydrolysing)) Ligase)/HCS (Holocarboxylase Synthetase). Upon addition of Biotin as a co-factor, the Apocarboxylases are converted into active Holocarboxylases. For HLCS, Biotin addition occurs as an ATP-dependent, two-step reaction that, in the first step, involves synthesis of the intermediate, Biotinyl-5-AMP. In the second step, Biotinyl-5-AMP is used to transfer Biotin, with release of AMP, to a specific Lysine residue in a highly conserved region in Apocarboxylases. Biotin enters into to the human body through food and is also synthesized by the normal microflora of the large intestine, where it is partly absorbed by Colonocytes (Ref.1 & 2).

Unlike Bacteria, higher organisms are unable to synthesize Biotin and thus depend entirely on the Vitamins present in foods to satisfy their Vitamin requirements. Biotin is present in very low concentrations in nature, thus putting the metabolic homeostasis of the cell at risk. To deal with their Biotin requirements, higher organisms have evolved to a very efficient and complex Biotin cycle to ensure adequate supply and utilization of the Vitamin (Ref.2 & 3). Most Biotin present in foods is not readily available because it is protein-bound and must be released from the Holocarboxylases to which it is attached before it can be used in Carboxylation reactions. This reaction is carried out by Peptide Hydrolases and pancreatic Btd (Biotinidase), which specifically cleaves the quasi-peptide bond between Biotin and Epsilon-amino group of L-Lysine residue to which it is attached in the Biocytin (Biotin-Lysine) complex. Biotin released in intestinal lumen is actively absorbed in a sodium-dependent fashion across the brush-border membrane of enterocytes. Once inside the cell, Biotin is again covalently attached to Apocarboxylases by HLCS/HCS and the cycle continues. L-Lysine is further subjected to degradation. During turnover of Carboxylases, Biotinylated peptides are then cleaved by cytoplasmic or plasma Btd thus allowing Biotin to be recycled and used in Biotinylation of new Carboxylases (Ref.3).

The importance of this cycle in maintaining Biotin levels within the cell is evidenced by the fact that mutations in either Btd or HLCS/HCS results in a potentially lethal metabolism disorder. Autosomal recessive disorders of Biotin metabolism in humans result from Btd or HLCS/HCS activity disruption. Impairment of Biotin transport leads to MCD (Multiple Carboxylase Deficiency). A defect of Btd activity blocks Biotin release from food or food recycling after Carboxylase proteolysis. This results in a secondary Biotin deficiency, disrupting all Carboxylase activity (Ref.3). Btd deficiency include Alopecia, Organic Aciduria, Seizures, Skin rash, mild Hyperammonemia and breathing problems. Biochemical and clinical manifestations of HLCS/HCS disorder include Ketolactic Acidosis, Organic Aciduria, Hyperammonemia, Skin rash, Feeding problems, Hypotonia, Seizures, Alopecia and Coma. Biotin metabolism disorder also results in BGD (Basal Ganglia Disease). BGD is associated with destruction of caudate heads centrally and partial or complete loss of the putamen. Symptoms observed in these patients include Confusion, Lethargy progressing to Coma, Vomiting, Seizures, Dystonia, Dysarthia, Dysphagia, Quadriparesis, Ataxia, Hypertension, and Chorea (Ref.3 & 4).


Recent study reveals that Biotin may play a role in other cellular events in eukaryotic organisms such as transcriptional or translational regulation or enhancement of activity of different Hepatic enzymes. In these studies, Biotin appears to augment Glucokinase enzymatic activity and transcription of its gene. Thus it is proposed that Biotin has different roles in the cell from those of its function as Carboxylase cofactor. Although Biotin and its role in classical cell metabolism have been known for decades, it is only now that researchers have begun to understand the multiple functions that this Vitamin has and the versatility of the enzymes involved in its metabolism (Ref.2 & 4). It is necessary to determine the effect of Biotin during development and disease to understand the different roles of this Vitamin in the organism and to assess the real risk kof a low-Biotin diet during pregnancy. The new functional data on the activity of Btd as a Biotinyltransferase that modifies Histones and therefore potentially impact gene regulation in a more broad sense also require further study (Ref.4).