Metabolic functions of biotin in the human body

1. Metabolic functions of biotin
Domina Petric, MD

2. • 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.
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
2
Metabolic roles

3. Biotin also has additional metabolic functions:
• regulator of gene expression
• substrate for the modification of
proteins by biotinylation
• regulation of the cell cycle
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
3
Metabolic roles

4. 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
5´-adenylate
• Covalent attachment of the vitamin to the
apocarboxylase with the release of AMP
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
4
Biotin holoenzyme synthetase

5. April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
5
Carboxylases

6. • Occurs at the carboxylase subsite.
• It involves the enzymatic
carboxylation of biotin using the
bicarbonate/ATP system as the
carboxyl donor.
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
6
First reaction (biotin carboxylase)

7. Occurs at the carboxyl transferase
subsite.
It involves transfer of the carboxyl
group from carboxybiotin to the
acceptor substrate.
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
7
Following step (carboxyl transferase)

8. • 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.
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
8
Carboxylases

9. April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
9
Biotin-dependent carboxylases

10. • 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.
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
10
Pyruvate carboxylase

11. Catalyzes the first committed
step in the synthesis and
elongation of fatty acids.
Biotin deficiency results in
impaired lipid metabolism.
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
11
Acetyl-CoA carboxylase

12. • 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.
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
12
Propionyl-CoA carboxylase

13. • It degrades the ketogenic amino
acid, leucine.
• Loss of its activity results in the shunting
of the leucine degradation product
3-methylcrotonyl CoA through an
alternate catabolic pathway to
3-hydroxyisovaleric acid, which is
excreted in the urine.
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
13
3-Methylcrotonyl-CoA carboxylase

14. Propionyl-CoA carboxylase
Catalyzes the oxidation
of odd-chain fatty acids.
Pyruvate carboxylase
Key enzyme in
gluconeogenesis.
Acetyl-CoA carboxylase
Catalyzes the first committed
step in the synthesis and
elongation of fatty acids.
3-Methylcrotonyl-CoA
carboxylase
It degrades leucine.
B7
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
14
Biotin-dependent carboxylases

15. April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
15
Gene
expression

16. • 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.
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
16
Biotinyl AMP and cGMP

17. 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
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
17
Nuclear factor NFκB

18. • 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.
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
18
Sp1 and Sp3

19. Biotin deficiency has been
shown to activate the signaling
by tyrosine kinases, which may
contribute to increasing SMVT-
mediated biotin uptake.
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
19
Receptor tyrosine kinases
Sodium-Dependent Vitamin Transporter (SMVT)

20. April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
20
Biotinylation of proteins and cell cycle

21. 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.
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
21
Biotinylation of proteins

22. 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.
April 19, 2018
Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
22
Cell cycle

23. • Combs GF. The Vitamins. Fundamental Aspects
in Nutrition and Health. Elsevier Inc. 2008.
Literature
April 19, 2018 23