CmcI, cephamycin biosynthesis-related enzyme
Human health is threatened by various pathogens, disease-causing organisms or other agents. The most familiar pathogens are viruses and bacteria. Viruses cause disease such as AIDS, smallpox, and common cold. Viruses are essentially fragments of nucleic acid (DNA or RNA), wrapped in a protective shell of proteins. They use the basic transcription and translation machinery of their host cells for their replication. Vaccines are used for the prevention of viral infections. Vaccine is a suspension of attenuated or killed microorganisms (viruses, bacteria) used to stimulate the synthesis of antibodies in human body before real attack of viruses.
On the other hand, the other pathogens, bacteria, are usually free-living cells, which perform most of their metabolic functions themselves, relying on the host (human) primarily for nutrition. Some bacteria have developed the ability to cause disease in humans, which can be a serious problem for humans. To destroy those bacteria, antibiotics, usually a product of a particular microorganism or plant, are used. Penicillin, small organic compound, was the one of the first antibiotics used to treat infections in humans, effectively used during World War II to cure injured soldiers who were infected with bacteria.
The battles between humans and bacteria continue endlessly. When human started to use antibiotics such as penicillin, which has beta-lactam ring in the structure, bacteria also created a new strategy to destroy penicillin by making a new enzyme, beta-lactamase, which destroys the beta-lactam ring of penicillin. This means penicillin does not work anymore as medicine. Therefore, a little modified penicillin, cephamycins, to escape the attack from beta-lactamases was discovered. Cephamycins are beta-lactam antibiotics substituted with a methoxyl group at the 7 alpha-position of the cephalosporins, precursor of cephamycins, which are closely related to penicillin. The reaction to put methoxyl group is done via two step reactions, hydroxylation and methylation, and two enzymes (CmcI and CmcJ) were thought to work for these continuous reactions.
The structure shown here is a complex of CmcI from Streptomyces clavuligerus with S-adenosyl-L-methonine (SAM), source of methyl group, and the demethylated product, and magnesium ion. The protein is a hexamer, arranged as a trimer of dimers, and has the shape of a puckered doughnut. C-terminal domain has modified alpha/beta fold (Rossmann-fold) common to nucleotide binding proteins. This structure is similar to the common binding mode of this co-factor in SAM-dependent methyltransferases, suggesting that CmcI is a methyltransferase.
Protein Data Bank (PDB)
Oster, L.M. Lester, D.R. Terwisscha Van Scheltinga, A. Svenda, M. Van Lun, M. Genereux, C. Andersson, I.; "Insights Into Cephamycin Biosynthesis: The Crystal Structure of Cmci from Streptomyces Clavuligerus."; J.Mol.Biol.; (2006) 358:546-. PubMed:16527306
author: Sachiyo Nomura