Official Full Name
Chloramphenicol Acetyltransferase
Background
Chloramphenicol acetyltransferase (or CAT) is a bacterial enzyme (EC 2.3.1.28) that detoxifies the antibiotic chloramphenicol and is responsible for chloramphenicol resistance in bacteria. This enzyme covalently attaches an acetyl group from acetyl-CoA to chloramphenicol, which prevents chloramphenicol from binding to ribosomes. A histidine residue, located in the C-terminal section of the enzyme, plays a central role in its catalytic mechanism.
Synonyms
Acetyl-CoA:chloramphenicol 3-O-acetyltransferase; CAT; 9040-07-7; chloramphenicol acetyltransferase; chloramphenicol acetylase; chloramphenicol transacetylase; CAT I; CAT II; CAT III
Abstract
Chloramphenicol (Cm) and its fluorinated derivative florfenicol (Ff) are potent inhibitors of bacterial protein biosynthesis. Due to the widespread use of Cm in human and veterinary medicine, bacterial pathogens of various species and genera have developed or acquired Cm resistance. Ff is used only in veterinary medicine and was introduced to the clinic in the mid-1990s. Of the Cm resistance genes known to date, only a few also mediate resistance to Ff. Different mechanisms exist for resistance to Cm and Ff, involving two chloramphenicol acetyltransferases (CATs) that require special attention. Phylogenetic trees of different CAT proteins and export proteins were constructed based on a multisequence alignment.
Use in human and veterinary medicine
Cm and some of its derivatives, including thiamphenicol and azidamfenicol, have been widely used in human medicine for many years. Certain esters of Cm, such as Cm succinate or Cm palmitate, are now produced in large quantities for therapeutic application. They have no antimicrobial activity until Cm is released after hydrolysis by esterases. Cm succinate exhibits good solubility in water and is therefore used for parenteral applications. Cm was considered a promising broad-spectrum antibiotic in the first few years after its introduction into the clinic until after the mid-1960s, many adverse effects associated with Cm application were gradually observed.
These side effects include dose-unrelated irreversible aplastic anemia, dose-related reversible bone-marrow suppression, or Gray's syndrome in neonates and infants. Rashes and allergic reactions are occasionally observed. Cm readily crosses the blood-brain barrier, so it remains an alternative treatment agent for meningitis caused by susceptible strains of Haemophilus influenzae, Streptococcus pneumoniae, or Neisseria meningitidis, as other antimicrobials cannot be used. Currently, Cm use in veterinary medicine is limited to pets and non-food-producing animals, and it was banned in 1994 in any food-producing animal in the EU because consumers could be adversely affected by the residue of food animals.
Figure 1. Structure of chloramphenicol and related substances (Schwarz, S.; et al. 2004)
Chloramphenicol acetyltransferase
Cm acetyltransferases (CATs) are able to inactivate Cm as well as thiamphenicol and azidamfenicol. As the hydroxyl group at C-3 in Ff is replaced by a fluor residue, its acceptor site for acetyl groups is structurally altered, which makes Ff resistant to CAT enzymes. Currently, CATs are divided into two types with distinctly different structures: the classic CAT, also known as type A CAT, and the novel CAT, also known as xenobiotic CAT or type B CAT.
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Type A chloramphenicol acetyltransferases
Type A CATs have been found in a variety of bacteria, and despite differences in their amino acid sequences, they still share some properties. The native CAT typically consists of three identical polypeptides between 207 and 238 amino acids (aa) in size. The cat gene encodes for the CAT monomer. Among all currently known type A CATs, those amino acids involved in substrate binding, catalytic activity, monomer folding or monomer assembly into trimers appear to be conserved. Some type A CATs have specific properties, such as the ability to mediate resistance to fusidic acid or sensitivity to inhibition by thiol-reactive reagents.
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Type B chloramphenicol acetyltransferase
Type B CAT, sometimes called xenobiotic acetyltransferase, also inactivates Cm by acetylation. Type B CAT shares some similarities with type A CAT: native type B CAT is also a homotrimer consisting of monomers in the range 209-212 aa. However, type B CAT differs significantly from type A CAT in its structure and appears to be related to other acetylating enzymes of staphylococci and enterococci. There are at least five distinct groups of type B cat genes: B-1-B-5. The first type B cat gene catB1 discovered was cloned from the chromosome of A. tumefaciens. The catB2 gene was found on the multiresistance transposon Tn 2424 of E. coli. The group B-3 contains a number of genes hitherto known as catB3 - catB6 and catB8, which are commonly associated with multiresistance transposons.
Figure 2. Phylogenetic tree of the class B CATs (Schwarz, S.; et al. 2004)
References
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Schwarz, S.; et al. Molecular basis of bacterial resistance to chloramphenicol and florfenicol. FEMS Microbiology Reviews. 2004.
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Leslie, A.G.W. Refined crystal structure of chloramphenicol acetyltransferase at 1.75 Å resolution. J. Mol. Biol. 1990.