Biotin Metabolism in S. cerevisiae
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Biotin Metabolism in S. cerevisiae

In unicellular eukaryotes like S. cerevisiae (Saccharomyces cerevisiae), Biotin or Vitamin-H, a member of B-Complex group of Vitamins acts as a cofactor for a few essential enzymes of the Carboxylase family. It is also required for the biosynthesis of fatty acids and the metabolism of amino acids and carbohydrates. Some organisms, including higher plants and most fungi and bacteria, are prototrophic for Biotin. Others, including most vertebrates and some bacteria, rely on exogenous sources (Ref.1 & 2). In mammals, Biotin is supplied by intestinal bacteria. Biotin is a colorless Vitamin and Orthorhombic when crystallized. It consists of two fused rings: an Imidazol (Ureido) and a Sulfur-containing (Tetrahydrothiophene) ring; and the latter is extended via a Valeric acid side chain, which is attached in a cis-configuration with respect to the Ureido ring. Both rings are fused in cis. Biotin contains three chiral carbon atoms, resulting in eight possible Stereoisomers. The d-Biotin only possesses Vitamin activity. The chemical name for the cofactor is: Hexahydro-2-Oxo-1H-Thieno (3,4-D) Imidazole-4-Pentanoic Acid. Biotin withstands high temperatures. Biotin metabolism is best understood in few bacteria like E. coli (Escherichia coli), B. subtilis (Bacillus subtilis), B. sphaericus (Bacillus sphaericus) and R. loti (Rhizobium loti). However S. cerevisiae is auxotrophic for Biotin and carries out synthesis through addition of the Biotin vitamers to the medium (Ref.1).

In S. cerevisiae, neither Pimelate nor Pimeloyl-CoA (Pimeloyl Coenzyme-A) is associated with growth. As S. cerevisiae is auxotrophic for Biotin, growth is complemented by the presence of the Biotin vitamers like KAPA (7-Keto-8-Aminopelargonic Acid), DAPA (7,8-Diaminopelargonic Acid), or Dethiobiotin to the medium or surroundings. The Biotin biosynthesis in S. cerevisiae starts with incorporation of precursors from the growth medium. KAPA is transported into the Yeast cell by the action of Bio5, which acts as a KAPA Transporter. Inside the Yeast cells KAPA is converted to DAPA by BioA/Bio3 protein or DAPA Aminotransferase (Ref.2). DAPA Aminotransferase is a Pyridoxal-5-Phosphate dependent enzyme and requires S-AdoMet (S-Adenosylmethionine) as Amino-group donor, an unusual feature among Aminotransferases. In the penultimate step DAPA is converted to Dethiobiotin by DtbS (Dethiobiotin Synthetase). This enzyme catalyzes the ATP (Adenosine Triphosphate)-dependent formation of Dethiobiotin from DAPA and Carbondioxide. In the last step in Biotin synthesis, which is least understood, is the conversion of Dethiobiotin to Biotin by the Biotin Synthetase (BioB/Bio2 protein). Again the covalent addition of Biotin to proteins is catalyzed by Biotin-Protein Ligase. For Biotin-Protein Ligase, 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 Apocarboxylase. Upon addition of Biotin as a co-factor, the Apocarboxylase are converted into active Holocarboxylase. The role of Biotin in Carboxylases is to act as vector for carboxyl-group transfer between donor and acceptor molecules during Carboxylation reaction. Protein-bound Biotin must be released from the Holocarboxylases to which it is attached before it can be used again in Carboxylation reactions and this release is facilitated by Peptide Hydrolases and results in the formation of Biocytin (Biotin-Lysine) complex (Ref.3).

The behavior of S. cerevisiae towards Biotin appears quite intriguing. Living organisms are either prototrophic for Biotin or manifest an absolute requirement for this Vitamin. S. cerevisiae needs an external supply of Biotin, a requirement that is met by the addition of the Biotin vitamers KAPA, DAPA or Dethiobiotin, but not by Pimelic acid nor Pimeloyl-CoA. S. cerevisiae performs the last three steps of Biotin biosynthesis. Besides, KAPA, DAPA and Dethiobiotin are not very widespread in nature and, indeed, they occur only in the Biotin metabolism pathway (Ref.2). The conservation, at least in part, of the Biotin biosynthesis capacity seems paradoxical in S. cerevisiae. S. cerevisiae Biotin gene (bio) cluster Bio3-4-5 is located on Chromosome-XIV, whereas Bio2, which encodes for the so-called Biotin Synthase, is located on Chromosome-X. The intergenic region within the Biotin cluster is remarkably small: 221 nucleotides between Bio3 and Bio4 ‘Start’ codons and 53 bp (53 Base Pairs) between Bio4 and Bio5. The two intergenic regions contain consensus sequences for transcription initiation and TATA boxes. Nonetheless, the remarkable compactness of the S. cerevisiae Biotin cluster strongly suggests a common regulation of its three genes. As there are no Bio5 gene equivalents in the E. coli and Bacilli genomes, S. cerevisiae may have conserved this gene through evolution, perhaps for rescue purposes, as it did for the three last steps of Biotin biosynthesis (Ref.2 & 3).