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Departments of a Human Genetics, b Pediatrics, and c Biochemistry and Molecular Biophysics, Medical College of Virginia at Virginia Commonwealth University, Richmond, VA 23298
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ABSTRACT |
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 TOP ABSTRACT INTRODUCTIONBIOTIN AS COENZYME FOR...BIOTINIDASE DEFICIENCYBIOTINIDASE HYDROLASE ACTIVITYBIOTINIDASE AS A BIOTIN-BINDING...FORMATION OF BIOTINYL...BIOTINIDASE BIOTINYL-TRANSFERASE...PHYSIOLOGIC ROLE FOR...PHYSIOLOGIC ROLE OF BIOTINYLATED...REFERENCES |
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KEY WORDS: • biotin • biotinidase • histones • hydrolase • transferase
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONBIOTIN AS COENZYME FOR...BIOTINIDASE DEFICIENCYBIOTINIDASE HYDROLASE ACTIVITYBIOTINIDASE AS A BIOTIN-BINDING...FORMATION OF BIOTINYL...BIOTINIDASE BIOTINYL-TRANSFERASE...PHYSIOLOGIC ROLE FOR...PHYSIOLOGIC ROLE OF BIOTINYLATED...REFERENCES |
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)
stimulated interest in determining its role in metabolism and disease
processes. Once biotin was shown to be the coenzyme for carbon
dioxide–fixing carboxylases, there were few additional studies to
determine if the vitamin had any other functions. Recently, we have
found evidence for a new activity of biotinidase with potentially new
roles in biotin metabolism. |
BIOTIN AS COENZYME FOR CARBOXYLASES |
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TOPABSTRACTINTRODUCTIONBIOTIN AS COENZYME FOR...BIOTINIDASE DEFICIENCYBIOTINIDASE HYDROLASE ACTIVITYBIOTINIDASE AS A BIOTIN-BINDING...FORMATION OF BIOTINYL...BIOTINIDASE BIOTINYL-TRANSFERASE...PHYSIOLOGIC ROLE FOR...PHYSIOLOGIC ROLE OF BIOTINYLATED...REFERENCES |
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, Lane et al. 1964
). Therefore, any
endogenous biotinylated molecules found in biological samples were
thought to be biotinylated subunits of carboxylases. In one study that
used radioactive biotin, some of the biotinylated proteins found in
3T3-L1 mouse fibroblast cells had molecular masses different from those
of the carboxylase subunits (Chandler and Ballard 1986
). Several of
these proteins were considered proteolytic degradation products of
carboxylases; others could not have been. No functions were attributed
to these biotinylated proteins, and they were not identified.
Three of the carboxylases are found in mitochondria and one in the
cytoplasm. Therefore, biotinylated proteins were expected to be found
only in the cytoplasm or in mitochondria. When avidin, a protein with a
very strong affinity to biotin, detected biotinylated material in
nuclei, this was immediately considered to represent nonspecific
binding. This nonspecific binding was attributed to electrostatic
interaction, differences in batches of avidin (Wood and Warnke 1981
),
the oligosaccharides of avidin (Updyke and Nicolson 1984
) and method of
tissue fixation (Green et al. 1992
, Kuhn 1988
).
When avidin was used to detect experimentally produced
biotinyl-proteins in histochemical studies, the endogenous biotin was
considered a nuisance, with multiple papers describing methods for
eliminating this "background." Few studies have attempted to
characterize this endogenous biotin even though biotin stores have been
found in clara and type II alveolar cells of rodent lungs (Kuhn 1988
),
in glandular elements and ducts of human salivary glands (Cauli et al. 1994
), in human thyroid, breast and various glandular tissues (Green et al. 1992
), and in liver (Shriver et al. 1993
) and kidney (Wood and Warnke 1981
).
The consequences of biotin deficiency in animals were observed after
the feeding of raw egg white, which contains large quantities of avidin
(Parsons et al. 1937
). Biotin deficiency can be induced in humans by
feeding them diets consisting of foods low in biotin and supplemented
with raw egg whites. Symptoms are reversed by returning biotin to the
diet. Biotin deficiency has also been observed in children who have the
inherited metabolic disorder, biotinidase deficiency.
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BIOTINIDASE DEFICIENCY |
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TOPABSTRACTINTRODUCTIONBIOTIN AS COENZYME FOR...BIOTINIDASE DEFICIENCYBIOTINIDASE HYDROLASE ACTIVITYBIOTINIDASE AS A BIOTIN-BINDING...FORMATION OF BIOTINYL...BIOTINIDASE BIOTINYL-TRANSFERASE...PHYSIOLOGIC ROLE FOR...PHYSIOLOGIC ROLE OF BIOTINYLATED...REFERENCES |
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). Biotinidase
deficiency is inherited as an autosomal recessive trait with variable
expression and age of onset. Clinical features of biotinidase
deficiency usually develop between 2 and 5 mo of age, but they may not
occur until early adolescence. Symptoms of the disorder include
seizures, hypotonia, ataxia, skin rash, hair loss, mental retardation,
ketolactic acidosis and organic aciduria. Administering pharmacologic
doses of biotin resolves many symptoms and prevents symptoms from
developing. Developmental delay, hearing loss and eye problems are
usually not reversible after biotin treatment.
Because symptoms of biotinidase deficiency can be prevented by early
institution of biotin, newborn screening for biotinidase deficiency is
conducted in many states and countries. The most common assay for
biotinidase deficiency measures the quantity of
p-aminobenzoate (PABA) produced from the hydrolysis of
biotinyl-PABA (Wolf et al. 1986
).
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BIOTINIDASE HYDROLASE ACTIVITY |
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TOPABSTRACTINTRODUCTIONBIOTIN AS COENZYME FOR...BIOTINIDASE DEFICIENCYBIOTINIDASE HYDROLASE ACTIVITYBIOTINIDASE AS A BIOTIN-BINDING...FORMATION OF BIOTINYL...BIOTINIDASE BIOTINYL-TRANSFERASE...PHYSIOLOGIC ROLE FOR...PHYSIOLOGIC ROLE OF BIOTINYLATED...REFERENCES |
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). The concentration of biocytin in serum is in the nanomolar
range, whereas biotinidase affinity constants for both biocytin and
biotinyl-PABA are in the micromolar range (Chauhan and Dakshinamurti 1988
). These authors also suggested that if the hydrolysis of biocytin
is a major function of biotinidase, a modifier molecule must be present
to lower the Km. These authors noted that the
concentration of biotinidase in serum is greater than that of biotin.
This made biotinidase a good candidate for action as a biotin-binding
or biotin carrier protein. |
BIOTINIDASE AS A BIOTIN-BINDING OR CARRIER PROTEIN |
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TOPABSTRACTINTRODUCTIONBIOTIN AS COENZYME FOR...BIOTINIDASE DEFICIENCYBIOTINIDASE HYDROLASE ACTIVITYBIOTINIDASE AS A BIOTIN-BINDING...FORMATION OF BIOTINYL...BIOTINIDASE BIOTINYL-TRANSFERASE...PHYSIOLOGIC ROLE FOR...PHYSIOLOGIC ROLE OF BIOTINYLATED...REFERENCES |
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). Biotinidase may bind biotin, thereby preventing it from
being excreted. Results of studies to determine biotin binding by serum
proteins have been equivocal. One study showed that most of the biotin
in human plasma is not bound to protein (Mock and Malik 1992
), whereas
another showed that, at pH 7, biotinidase was the only protein in serum
that binds biotin, with two Kd for biotin, both
in the nanomolar range (Chauhan and Dakshinamurti 1988
).
The specific binding of avidin-biotin complex with hepatic plasma
membrane, which is insensitive to neuraminidase action, suggested that
this complex mimicked a natural biotin carrier protein (Chaulifour and Dakshinamurti 1983
). A biotin receptor was later isolated from liver
plasma membrane (Vesely et al. 1987
). Studies of impaired intestinal
absorption of biotin in a child with biotinidase deficiency suggested
that normal biotin uptake is the result of two systems, one which is
saturable at a low Km; the other is passive with
a high Km (Thoene et al. 1983
). Biotin is taken
up by a Na+-dependent cotransport system in human
intestinal brush border membranes (Said et al. 1987
).
How can biotinidase act as a carrier protein? Because biotinidase is
inhibited by inhibitors of thiols, such as hydroxymercuribenzoate, the
enzyme active site must contain an active cysteine (Pispa 1965
).
Therefore, the cleavage of biocytin may occur through the formation of
an acyl enzyme with the biotin attached through a thioester to
biotinidase.
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FORMATION OF BIOTINYL-BIOTINIDASE |
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TOPABSTRACTINTRODUCTIONBIOTIN AS COENZYME FOR...BIOTINIDASE DEFICIENCYBIOTINIDASE HYDROLASE ACTIVITYBIOTINIDASE AS A BIOTIN-BINDING...FORMATION OF BIOTINYL...BIOTINIDASE BIOTINYL-TRANSFERASE...PHYSIOLOGIC ROLE FOR...PHYSIOLOGIC ROLE OF BIOTINYLATED...REFERENCES |
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first demonstrated that biotinidase can form an
acyl-biotinyl-biotinidase. In these studies, when biotinidase cleaves
biotinyl-PABA or biocytin in the presence of hydroxamate,
biotinyl-hydroxamate is formed. We proposed that during biotinidase
hydrolysis of biocytin, the carboxyl group of the biotin forms an
acyl-biotinidase through the thiol group of a cysteine in the active
site (Fig. 1
).
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). This suggests that in serum at pH 7.4,
biotinidase cleaves biocytin, but the biotin is not released. Instead
biotinidase forms an acyl-enzyme complex. The stability of the
thioester bond at 
pH 7 allows biotinidase to act as a carrier protein
in serum. Either low pH or nucleophiles, such as hydroxylamine, can
remove the biotin from the enzyme, thereby permitting biotinidase to
interact with another biocytin molecule (Fig. 3
).Hydroxylamine is known to hydrolyze thioester bonds nonspecifically.
Can biotinidase transfer biotin to a specific acceptor?
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BIOTINIDASE BIOTINYL-TRANSFERASE ACTIVITY |
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TOPABSTRACTINTRODUCTIONBIOTIN AS COENZYME FOR...BIOTINIDASE DEFICIENCYBIOTINIDASE HYDROLASE ACTIVITYBIOTINIDASE AS A BIOTIN-BINDING...FORMATION OF BIOTINYL...BIOTINIDASE BIOTINYL-TRANSFERASE...PHYSIOLOGIC ROLE FOR...PHYSIOLOGIC ROLE OF BIOTINYLATED...REFERENCES |
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). To show that biotinidase was responsible for the
biotinylation of histone, calf thymus histone H2A was incubated in the
presence or absence of biocytin, with normal serum and with serum from
an individual with profound biotinidase deficiency. The various
mixtures were then run on SDS-PAGE and biotinylated histones were
detected as described above. Histones are biotinylated when incubated
with biocytin in presence of normal serum, but not with
biotinidase-deficient serum. Biotinylated histones increased linearly
with time and with biotinidase concentration.
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, Freytag and Utter 1983
). The
biotinyl-transferase assay is much more sensitive than the biotinidase
hydrolase assay. Transferase can be detected with as little as 1 nL of
normal serum, whereas hydrolase detection requires 100 µL of serum
per assay (Hymes et al. 1995a
). Biotinidase biotinyl-transferase
activity was measured in sera from two groups of children with profound
biotinidase deficiency, those ascertained by having symptoms and those
detected by newborn screening (Hymes et al. 1995b
). Sera from all
symptomatic children had no biotinyl-transferase activity, whereas sera
from two thirds of the children ascertained by newborn screening had
variable, but detectable, biotinyl-transferase activity. Therefore,
biotinidase apparently has two distinct functions, acting as
biotinyl-hydrolase or as biotinyl-transferase, depending on the pH of
the cell compartment and the availability of specific acceptors. To
date, the only protein found to be a specific acceptor for biotin from
biotinyl-biotinidase is histone. Histones H2A, H2B, H1, H2 and H3 are
all biotinylated when incubated with biotinidase and biocytin at pH
>7. Do these biotinylated histones function in the nucleus? |
PHYSIOLOGIC ROLE FOR BIOTINYLATED HISTONE IN THE NUCLEUS |
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TOPABSTRACTINTRODUCTIONBIOTIN AS COENZYME FOR...BIOTINIDASE DEFICIENCYBIOTINIDASE HYDROLASE ACTIVITYBIOTINIDASE AS A BIOTIN-BINDING...FORMATION OF BIOTINYL...BIOTINIDASE BIOTINYL-TRANSFERASE...PHYSIOLOGIC ROLE FOR...PHYSIOLOGIC ROLE OF BIOTINYLATED...REFERENCES |
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). In
these studies, the nuclei were isolated at pH 7.8. In another study in
rats that was similar but in which the nuclear fraction was isolated in
sucrose and magnesium without a buffer, essentially no biotin was found
in the nuclear fraction (Petrelli et al. 1978b
). Biotin has been
detected using avidin and antibiotin antibody in optically clear nuclei
(OCN) in neoplastic tissue, including pulmonary endodermal tumors
(Nakatani et al. 1994
), endometroid adenocarcinoma of the ovary
(Tsujimoto et al. 1991
) and in papillary carcinomas of the thyroid
(Yamashita et al. 1992
). Biotin-rich OCN are also found in normal
endometrial glandular epithelium during pregnancy (Yokoyama et al. 1993
).
Biotin must have a specific role in the nucleus. Biotin has been shown
to regulate the transcription of glucokinase synthesis (Chauhan and Dakshinamurti 1991
). Biotin may play a role in the packaging of DNA
because histones have been shown to dissociate from the DNA in
biotin-deficient rats (Petrelli et al. 1976
). Biotin deficiency also
resulted in decreased phosphorylation and methylation and increased
acetylation of histones compared with that of normal rats (Petrelli et al. 1978a
). The unique arrangement of chromatin substructures in
biotin-rich OCN may be related to the modifying effects biotin has on
the structure of histones (Nakatani et al. 1994
). Histones are also
found outside of the nucleus.
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PHYSIOLOGIC ROLE OF BIOTINYLATED HISTONES OUTSIDE THE NUCLEUS |
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TOPABSTRACTINTRODUCTIONBIOTIN AS COENZYME FOR...BIOTINIDASE DEFICIENCYBIOTINIDASE HYDROLASE ACTIVITYBIOTINIDASE AS A BIOTIN-BINDING...FORMATION OF BIOTINYL...BIOTINIDASE BIOTINYL-TRANSFERASE...PHYSIOLOGIC ROLE FOR...PHYSIOLOGIC ROLE OF BIOTINYLATED...REFERENCES |
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, Koutsikos et al. 1990
), and
both stimulate cyclic GMP synthesis and nitrous oxide formation (Hu et al. 1995
, Spence and Koudelka 1984
). Biotin stimulates growth factor
production in certain cultured cells (Moskowitz and Cheng 1985
).
Histones H2A and H2B have thymus hormone activity (Reichhart et al. 1985
), and histone H4 fragments have growth factor activity (Bab et al. 1992
). Whether biotinylated histone or biotinylated histone fragments
are the active peptides in these systems remain to be determined.
Finding so many functions shared by biotin and histones suggests that
understanding biotinidase biotinyl-transferase action may help
elucidate how biotin regulates transcription and controls cellular
growth. We now have clues for the mechanisms of these functions.
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FOOTNOTES |
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1 Presented at the symposium "Nutrition,
Biochemistry and Molecular Biology of Biotin" as part of Experimental
Biology 98, April 18–22, 1998, San Francisco, CA. The symposium was
sponsored by the American Society for Nutritional Sciences and was
supported in part by an educational grant from Roche Vitamins and Fine
Chemicals. Published as a supplement to The Journal of
Nutrition. Guest editor for the symposium publication was Donald
Mock, University of Arkansas for Medical Sciences, Arkansas Children's
Hospital, Little Rock, AR.
2 Supported in part by National Institutes of
Health grants DK33840 and HD48258.
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REFERENCES |
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TOPABSTRACTINTRODUCTIONBIOTIN AS COENZYME FOR...BIOTINIDASE DEFICIENCYBIOTINIDASE HYDROLASE ACTIVITYBIOTINIDASE AS A BIOTIN-BINDING...FORMATION OF BIOTINYL...BIOTINIDASE BIOTINYL-TRANSFERASE...PHYSIOLOGIC ROLE FOR...PHYSIOLOGIC ROLE OF BIOTINYLATED...REFERENCES |
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