Info

aNormal ranges are reported (n = 15 for serum; n = 16 for urine, except biocytin, n = 10).

including unidentified biotin metabolites.

ND, not determined.

aNormal ranges are reported (n = 15 for serum; n = 16 for urine, except biocytin, n = 10).

including unidentified biotin metabolites.

ND, not determined.

between the carboxyl group of the valeric acid side chain of biotin and the "-amino group of a specific lysyl residue in the apocarboxylase; these regions contain sequences of amino acids that are highly conserved for the individual carboxylases both within and between species.

In the carboxylase reaction, the carboxyl moiety is first attached to biotin at the ureido nitrogen opposite the side chain; then the carboxyl group is transferred to the substrate. The reaction is driven by the hydrolysis of ATP to ADP and inorganic phosphate. Subsequent reactions in the pathways of the mammalian carboxylases release carbon dioxide from the product of the carboxylase reaction. Thus, these reaction sequences rearrange the substrates into more useful intermediates but do not violate the classic observation that mammalian metabolism does not result in the net fixation of carbon dioxide.

Regulation of intracellular mammalian carboxy-lase activity by biotin remains to be elucidated. However, the interaction of biotin synthesis and production of holoacetyl-CoA carboxylase in

Escherichia coli has been extensively studied. In the bacterial system, the apocarboxylase protein and biotin (as the intermediate biotinyl-AMP) act together to control the rate of biotin synthesis by direct interaction with promoter regions of the biotin operon, which in turn controls a cluster of genes that encode enzymes that catalyze the synthesis of biotin.

The five biotin-dependent mammalian carboxylases are acetyl-CoA carboxylase isoforms I and II (also known as a-ACC (EC 6.4.1.2) and p-ACC (EC 6.4.1.2)), pyruvate carboxylase (EC 6.4.1.1), methyl-crotonyl-CoA carboxylase (EC 6.4.1.4), and propio-nyl-CoA carboxylase (EC 6.4.1.3). ACC catalyzes the incorporation of bicarbonate into acetyl-CoA to form malonyl-CoA (Figure 2). There are two isoforms of ACC. Isoform I is located in the cytosol and produces malonyl-CoA, which is rate limiting in fatty acid synthesis (elongation). Isoform II is located on the outer mitochondrial membrane and controls fatty acid oxidation in mitochondria through the inhibitory effect of malonyl-CoA on fatty acid transport into mitochondria. An inactive mitochondrial form of ACC may serve as storage for biotin.

The three remaining carboxylases are mitochon-drial. Pyruvate carboxylase (PC) catalyzes the incorporation of bicarbonate into pyruvate to form oxaloacetate, an intermediate in the Krebs tricarboxylic acid cycle (Figure 2). Thus, PC catalyzes an anaplerotic reaction. In gluconeogenic tissues (i.e., liver and kidney), the oxaloacetate can be converted to glucose. Deficiency of PC is probably the cause of the lactic acidemia, central nervous system lactic acidosis, and abnormalities in glucose regulation observed in biotin deficiency and biotinidase deficiency. P-Methylcrotonyl-CoA carboxylase (MCC) catalyzes an essential step in the degradation of the branched-chain amino acid leucine (Figure 2). Deficient activity of MCC leads to metabolism of

Hydroxyisovaleric Acid
Figure 2 Interrelationship of pathways catalyzed by biotin-dependent enzymes (shown in boxes).

3-methylcrotonyl-CoA to 3-hydroxyisovaleric acid and 3-methylcrotonylglycine by an alternate pathway. Thus, increased urinary excretion of these abnormal metabolites reflects deficient activity of MCC.

Propionyl-CoA carboxylase (PCC) catalyzes the incorporation of bicarbonate into propionyl-CoA to form methylmalonyl-CoA; methylmalonyl-CoA undergoes isomerization to succinyl-CoA and enters the tricarboxylic acid cycle (Figure 2). In a manner analogous to MCC deficiency, deficiency of PCC leads to increased urinary excretion of 3-hydroxy-propionic acid and 3-methylcitric acid.

In the normal turnover of cellular proteins, holo-carboxylases are degraded to biocytin or biotin linked to an oligopeptide containing at most a few amino acid residues (Figure 1). Biotinidase releases biotin for recycling. Genetic deficiencies of holocarboxylase synthetase and biotinidase cause the two types of multiple carboxylase deficiency that were previously designated the neonatal and juvenile forms.

Was this article helpful?

0 0
Natural Weight Loss

Natural Weight Loss

I already know two things about you. You are an intelligent person who has a weighty problem. I know that you are intelligent because you are seeking help to solve your problem and that is always the second step to solving a problem. The first one is acknowledging that there is, in fact, a problem that needs to be solved.

Get My Free Ebook


Post a comment