Chapter 156

### Abstract

1. Biotin, a water-soluble vitamin belonging to the B complex, acts as a covalently bound coenzyme in each of five carboxylases in humans: pyruvate carboxylase, propionyl-CoA carboxylase, 3-methylcrotonyl-CoA carboxylase, and acetyl-CoA carboxylases 1 (alpha) and 2 (beta). These enzymes have important roles in gluconeogenesis, fatty acid synthesis, mitochondrial import of fatty acids, and amino acid catabolism. Biotin is derived from the diet and possibly also from the synthetic activity of gastrointestinal microflora.

2. Each of the carboxylases is synthesized as an inactive apoenzyme that is subsequently biotinylated through two partial reactions, each of which is catalyzed by the enzyme holocarboxylase synthetase. Acetyl-CoA carboxylase 1 functions principally in the cytoplasm, whereas the other four holocarboxylases function in mitochondria and the outer mitochondrial membrane. Ultimately, these enzymes are degraded proteolytically, probably by the lysosomal autophagic system. The biotin-containing products of degradation, biocytin (ɛ-N-biotinyl-L-lysine) and biotinyl peptides are acted on by biotinidase, which cleaves the amide bond between lysine and biotin. The liberated biotin is recycled and enters the free biotin pool. Biotinidase also has been shown, in presence of biocytin, to transfer biotin to nucleophilic acceptors, such as histones. This function appears to be an in vitro artifact with no physiological significance.

3. There are two major defects in the cycle of biotin utilization in humans. Both disorders result in multiple carboxylase deficiency. Holocarboxylase synthetase deficiency (MIM 253270), also known as early-onset (neonatal) multiple carboxylase deficiency based on the usual age of onset of symptoms, is a disorder of biotinylation. Biotinidase deficiency (MIM 253260), also known as late-onset (juvenile) multiple carboxylase deficiency, is a disorder of biotin recycling. Deficiencies of individual carboxylases are rare.

4. Holocarboxylase synthetase deficiency has been described in <100 children. Clinical symptoms include feeding and breathing difficulties, hypotonia, seizures, lethargy, sometimes progressing to coma, and developmental delay. Some children exhibit skin rash and alopecia. Affected children exhibit metabolic acidosis, organic aciduria, and mild to moderate hyperammonemia. The organic aciduria includes elevated concentrations of β-hydroxyisovalerate, β-methylcrotonylglycine, β-hydroxypropionate, methylcitrate, lactate, and tiglylglycine.

5. The enzyme defect has been demonstrated in lymphocytes, cultured fibroblasts, and cultured lymphoblasts from affected children. Holocarboxylase synthetase in the tissues of most of the children examined have increased Km values for biotin, although a few have been described with a normal Km and a decreased Vmax.

6. Holocarboxylase synthetase deficiency is inherited as an autosomal recessive trait. Heterozygosity cannot be confirmed by measuring enzymatic activity in the tissues of parents but should be determined by mutation analysis.

7. The normal mammalian enzyme has been purified and characterized biochemically, and multiple mutations within the synthetase gene have been identified. Some of these mutations occur within the biotin-binding domain and are likely responsible for the increased Km for biotin, explaining the biotin responsiveness that occurs in this disease. A mutation that results in an enzyme with a normal Km but decreased Vmax may also respond to biotin supplementation, and in such cases it is speculated that the enzyme conformation is favorably affected by super-physiologic biotin concentration. A single base deletion/null mutation has always been found in the compound heterozygous state, usually together with a mutation within the biotin-binding domain, but never homozygous, which may be lethal in utero. The expression of holocarboxylase synthetase is regulated by three promoters; promoter ...

Sign in to your MyAccess profile while you are actively authenticated on this site via your institution (you will be able to verify this by looking at the top right corner of the screen - if you see your institution's name, you are authenticated). Once logged in to your MyAccess profile, you will be able to access your institution's subscription for 90 days from any location. You must be logged in while authenticated at least once every 90 days to maintain this remote access.

Ok

## Subscription Options

### OMMBID Full Site: One-Year Subscription

Connect to the full suite of OMMBID content including new and revised chapters that reflect the latest research, image galleries, clinical phenotypes, and more.