1. Metabolic functions of biotin
Domina Petric, MD

2. Metabolic roles
Biotin functions in intermediary metabolism in the transfer of covalently bound, single-carbon units in the most oxidized form, CO2.
This function is implemented by a number of biotin-dependent carboxylases and in a number of other carboxylases, transcarboxylases and decarboxylases in microorganisms.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

3. Metabolic roles regulator of gene expression
Biotin also has additional metabolic functions:
regulator of gene expression
substrate for the modification of proteins by biotinylation
regulation of the cell cycle
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

4. Biotin holoenzyme synthetase
This enzyme catalyzes the formation of the linkage of the biotin prosthetic group to each apoenzyme covalently to the ε-amino group of a lysyl residue in two steps:
Activation of the vitamin as biotinyl ´-adenylate
Covalent attachment of the vitamin to the apocarboxylase with the release of AMP
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

5. Carboxylases
The catalytic action of each of the biotin-dependent carboxylases proceeds by way of a nonclassic, two-site, ping-pong mechanism, with partial reactions being performed by dissimilar subunits.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

6. First reaction (biotin carboxylase)
Occurs at the carboxylase subsite.
It involves the enzymatic carboxylation of biotin using the bicarbonate/ATP system as the carboxyl donor.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

7. Following step (carboxyl transferase)
Occurs at the carboxyl transferase subsite.
It involves transfer of the carboxyl group from carboxybiotin to the acceptor substrate.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

8. Carboxylases
These two subsites appear to be spatially separated in each enzyme.
The physicochemical mechanisms proposed for these reactions entail the transfer of biotinyl CO2 between subsites via movement of the prosthetic group back and forth by virtue of rotation of at least one of the 10 single bonds (probably C-2–C-6) on the valeryl lysyl side chain.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

9. Biotin-dependent carboxylases
The biotin-containing carboxylases have important functions in the metabolism of lipids, glucose, some amino acids and energy.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

10. Pyruvate carboxylase
It is a key enzyme in gluconeogenesis, along with phosphoenolpyruvate carboxykinase (PEPCK), to catalyze the formation of phosphoenolpyruvate from three-carbon precursors.
It also serves to replenish the mitochondrial supply of oxaloacetate to support the citric acid cycle as well as the formation of citrate for transport to the cytosol for lipogenesis.
Biotin deficiency can lead to fasting hypoglycemia and ketosis.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

11. Acetyl-CoA carboxylase
Catalyzes the first committed step in the synthesis and elongation of fatty acids.
Biotin deficiency results in impaired lipid metabolism.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

12. Propionyl-CoA carboxylase
Catalyzes the oxidation of odd-chain fatty acids produced by the degradation of the branched-chain amino acids as well as methionine and threonine, and by the gastrointestinal microflora.
The enzyme produces methylmalonyl-CoA, which is used for energy and glucose production.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

13. 3-Methylcrotonyl-CoA carboxylase
It degrades the ketogenic amino acid, leucine.
Loss of its activity results in the shunting of the leucine degradation product methylcrotonyl CoA through an alternate catabolic pathway to hydroxyisovaleric acid, which is excreted in the urine.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

14. Biotin-dependent carboxylases
Acetyl-CoA carboxylase
Catalyzes the first committed step in the synthesis and elongation of fatty acids.
Pyruvate carboxylase B7
Propionyl-CoA carboxylase
Key enzyme in gluconeogenesis.
Catalyzes the oxidation of odd-chain fatty acids.
3-Methylcrotonyl-CoA carboxylase
It degrades leucine.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

15. Gene expression
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

16. Biotinyl AMP and cGMP
It has been suggested that biotinyl AMP activates a soluble guanylate cyclase, which increases the synthesis of cGMP, stimulating protein kinase G and leading to phosphorylation and activation of proteins that increase the transcription of genes encoding biotin holoenzyme synthetase and some carboxylases.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

17. Nuclear factor NFκB
Biotin deprivation has been shown to increase:
nuclear translocation, binding and transcriptional activity of NFκB
nuclear contents of p50 and p65 and activities of IκBa kinases
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

18. Sp1 and Sp3
Biotin appears necessary for the expression of these transcription factors, which are associated with the expression of a cytochrome P450 gene and decreased transcription of the sarco/endoplasmic reticulum ATPase 3 gene.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

19. Receptor tyrosine kinases
Biotin deficiency has been shown to activate the signaling by tyrosine kinases, which may contribute to increasing SMVT-mediated biotin uptake.
Sodium-Dependent Vitamin Transporter (SMVT)
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

20. Biotinylation of proteins and cell cycle
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

21. Biotinylation of proteins
The addition of biotin to DNA-binding histone proteins appears to involve a biotin transferase function of biotinidase, which uses biocytin for this purpose.
Biotin may play a role in the packaging, transcription and/or replication of DNA to effect epigenetic regulation of gene function.
Among the gene products affected by biotin status are cytokines and their receptors, oncogenes, genes involved in glucose metabolism and genes that play a role in cellular biotin homeostasis.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

22. Cell cycle
Biotin has been shown to be necessary for the normal progression of cells through the cell cycle, with biotin-deficient cells arresting in the G1 phase.
Proliferating lymphocytes increase their activities of ß-methylcrotonyl-CoA carboxylase and propionyl-CoA carboxylase as well as their biotin uptake.
November 12, 2018
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc

23. Literature
Combs GF. The Vitamins. Fundamental Aspects in Nutrition and Health. Elsevier Inc
November 12, 2018