This entry represents the carboxypeptidase domain found in carboxypeptidase (CP) E (CPE, also known as carboxypeptidase H, and enkephalin convertase;(); MEROPS identifier M14.005). CPE belongs to subfamily M14B (N/E subfamily) of the M14 family of metallocarboxypeptidases (MCPs) []. It is an important enzyme responsible for the proteolytic processing of prohormone intermediates (such as pro-insulin, pro-opiomelanocortin, or pro-gonadotropin-releasing hormone) by specifically removing C-terminal basic residues []. In addition, it has been proposed that the regulated secretory pathway (RSP) of the nervous and endocrine systems utilizes membrane-bound CPE as a sorting receptor. A naturally occurring point mutation in CPE reduces the stability of the enzyme and causes its degradation, leading to an accumulation of numerous neuroendocrine peptides that result in obesity and hyperglycemia [, ]. Reduced CPE enzyme and receptor activity could underlie abnormal placental phenotypes from the observation that CPE is down-regulated in enlarged placentas of interspecific hybrid (interspecies hybrid placental dysplasia, IHPD) and cloned mice [].The carboxypeptidase A family can be divided into four subfamilies: M14A(carboxypeptidase A or digestive), M14B (carboxypeptidase H or regulatory), M14C (gamma-D-glutamyl-L-diamino acid peptidase I) and M14D (AGTPBP-1/Nna1-like proteins) [, ]. Members of subfamily M14B have longer C-termini than those of subfamily M14A [], and carboxypeptidase M (a member of the H family) is bound to the membrane by a glycosylphosphatidylinositol anchor, unlike the majority of the M14 family, which are soluble []. The zinc ligands have been determined as two histidines and a glutamate,and the catalytic residue has been identified as a C-terminal glutamate,but these do not form the characteristic metalloprotease HEXXH motif [, ]. Members of the carboxypeptidase A family are synthesised as inactive molecules with propeptides that must be cleaved to activate the enzyme. Structural studies of carboxypeptidases A and B reveal the propeptide to exist as a globular domain, followed by an extended α-helix; this shields the catalytic site, without specifically binding to it, while the substrate-binding site is blocked by making specific contacts [, ].
Clostridial species are one of the major causes of food poisoning/gastro-intestinal illnesses. They are Gram-positive, spore-forming rods that occur naturally in the soil []. Among the family are: Clostridium botulinum, which produces one of the most potent toxins in existence; Clostridium tetani, causative agent of tetanus; and Clostridium perfringens, commonly found in wound infections and diarrhoea cases. The use of toxins to damage the host is a method deployed by many bacterial pathogens.The major virulence factor of C. perfringens is the CPE enterotoxin, which is secreted upon invasion of the host gut, and contributes to food poisoning and other gastrointestinal illnesses []. It has a molecular weight of 35.3kDa, and is responsible for the disintegration of tight junctions between endothelial cells in the gut []. This mechanism is mediated by host claudins-3 and -4, situated at the tight junctions.Two more host receptors have been characterised and expressed in vivo[]. Named CPE-R and RVP1, these may be utilised in the passage of Clostridial species through the gut wall, although the regulatory mechanisms have not been elucidated.This entry also includes HA-70 from Clostridium botulinum C phage. The hemagglutinin (HA) components of the progenitor toxin protects the structural integrity of botulinum neurotoxin. The structure of HA70 from type C and D toxin (HA70/C/D) has been revealed [, ].
