<p>In the MEROPS database peptidases and peptidase homologues are grouped into clans and families. Clans are groups of families for which there is evidence of common ancestry based on a common structural fold:</p><ul> <li>Each clan is identified with two letters, the first representing the catalytic type of the families included in the clan (with the letter 'P' being used for a clan containing families of more than one of the catalytic types serine, threonine and cysteine). Some families cannot yet be assigned to clans, and when a formal assignment is required, such a family is described as belonging to clan A-, C-, M-, N-, S-, T- or U-, according to the catalytic type. Some clans are divided into subclans because there is evidence of a very ancient divergence within the clan, for example MA(E), the gluzincins, and MA(M), the metzincins.</li><li>Peptidase families are grouped by their catalytic type, the first character representing the catalytic type: A, aspartic; C, cysteine; G, glutamic acid; M, metallo; N, asparagine; S, serine; T, threonine; and U, unknown. The serine, threonine and cysteine peptidases utilise the amino acid as a nucleophile and form an acyl intermediate - these peptidases can also readily act as transferases. In the case of aspartic, glutamic and metallopeptidases, the nucleophile is an activated water molecule. In the case of the asparagine endopeptidases, the nucleophile is asparagine and all are self-processing endopeptidases. </li></ul><p>In many instances the structural protein fold that characterises the clan or family may have lost its catalytic activity, yet retain its function in protein recognition and binding. </p><p>Aspartic endopeptidases <db_xref db="EC" dbkey="3.4.23."/> of vertebrate, fungal and retroviral origin have been characterised [<cite idref="PUB00006548"/>]. More recently, aspartic endopeptidases associated with the processing of bacterial type 4 prepilin [<cite idref="PUB00020023"/>] and archaean preflagellin have been described [<cite idref="PUB00035904"/>, <cite idref="PUB00014343"/>].</p><p>Structurally, aspartic endopeptidases are bilobal enzymes, each lobe contributing a catalytic Asp residue, with an extended active site cleft localised between the two lobes of the molecule. One lobe has probably evolved from the other through a gene duplication event in the distant past. In modern-day enzymes, although the three-dimensional structures are very similar, the amino acid sequences are more divergent, except for the catalytic site motif, which is very conserved. The presence and position of disulphide bridges are other conserved features of aspartic peptidases.All or most aspartate peptidases are endopeptidases. These enzymes have been assigned into clans (proteins which are evolutionary related), and further sub-divided into families, largely on the basis of their tertiary structure.</p><p>This group of aspartic peptidases belong to MEROPS peptidase family A1 (clan AA, pepsin family). They are transmembrane aspartic endopeptidases which in human is a candidate beta-secretase in Alzheimer's disease (together with memapsin 1, <db_xref db="INTERPRO" dbkey="IPR009121"/>).</p><p>One of the major neuropathological hallmarks of Alzheimer's disease (AD)is the progressive formation in the brain of insoluble amyloid plaques and vascular deposits consisting of beta-amyloid protein (beta-APP) [<cite idref="PUB00013925"/>].Production of beta-APP requires proteolytic cleavage of the large type-1 transmembrane (TM) protein amyloid precursor protein (APP) [<cite idref="PUB00013732"/>]. This processis performed by a variety of enzymes known as secretases. To initiate beta-APP formation, beta-secretase cleaves APP to release a soluble N-terminal fragment (APPsBeta) and a C-terminal fragment that remains membrane bound. This fragment is subsequently cleaved by gamma-secretase to liberate beta-APP.</p><p>Several independent studies identified a novel TM aspartic protease as themajor beta-secretase [<cite idref="PUB00013926"/>, <cite idref="PUB00013927"/>, <cite idref="PUB00013928"/>]. This protein, termed Memapsin-2 or beta-site APP cleaving enzyme 1 (BACE1), shares 64% amino acid sequence similarity with a second enzyme, termed BACE2. Together, BACE1 and BACE2 define a novel family of aspartyl proteases [<cite idref="PUB00013929"/>]. Both enzymes share significant sequence similarity with other members of the pepsin family of aspartyl proteases and contain the two characteristic D(T/S)G(T/S) motifs that form the catalytic site. However, by contrast with other aspartyl proteases, BACE1 and BACE2 are type I TM proteins. Each protein comprises a large lumenal domain containing the active centre, a single TM domain and a small cytoplasmic tail.</p><p> Memapsin-2, has a broad tissue distribution, with brain expression levels moderately higher than those of peripheral tissues. Mice deficient in BACE1 are healthy, fertile, and appear normal in gross anatomy, tissue histology and clinical chemistry. BACE1 -/- mice that are also hemizygous for an amyloid precursor protein transgene lack brain beta-amyloid and beta-secretase-cleaved APP C-terminal fragments [<cite idref="PUB00013931"/>]. These findings substantiate the theory that BACE1 acts as the major beta-secretase in vivo, and suggest that therapeutic inhibition of BACE1 as a potential treatment for Alzheimer's disease may be free of mechanism- based toxicity.</p>