joining of several Aβ fragments together. Qui et al. hypothesized that the Aβ fragments generated by IDE can either enhance oligomerization of the Aβ peptide or can oligomerize themselves. It is also entirely possible that IDE could mediate the degradation and oligomerization of Aβ by independent actions that have yet to be investigated. Mechanism The mechanism of the IDE enzyme remains poorly understood. The first step of one proposed mechanism includes a zinc-bound hydroxide group performing a nucleophilic attack on a carbon substrate that materializes into the intermediate INT1. In this species, we can note that the zinc-bound hydroxide is completely transferred on the carbonyl carbon of substrate as a consequence of the Zn2+−OH bond breaking. In TS2, the Glu111 residue rotates to assume the right disposition to form two hydrogen bonds with the amide nitrogen and the −OH group linked to the carbon atom of substrate, thus behaving as hydrogen donor and acceptor, simultaneously. The formation of the second cited bond favors the re-establishment of the Zn2+−OH bond broken previously at the INT1 level. The nucleophilic addition and the protonation of peptide amide nitrogen is a very fast process that is believed to occur as a single step in the catalytic process. The final species on the path is the product PROD. As a consequence of transfer of the proton of Glu111 onto the amide nitrogen of substrate that occurred in TS3, the peptide N—C bond is broken. A look at the whole reaction path indicates that the rate-determining step in this process is the nucleophilic addition. After this point, the catalytic event should proceed without particular obstacles. Model organisms Model organisms have been used in the study of IDE function. A conditional knockout mouse line, called Idetm1a(EUCOMM)Wtsi was generated as part of the International Knockout Mouse Consortium program — a high-throughput mutagenesis project to generate and distribute animal models of disease to interested scientists. Male and female animals underwent a standardized phenotypic screen to determine the effects of deletion. Twenty three tests were carried out on mutant mice and two significant abnormalities were observed. Homozygous mutant animals displayed abnormal drinking behavior, and males also had an increased NK cell number. References External links The MEROPS online database for peptidases and their inhibitors: M16.002 Zinc enzymes Genes mutated in mice