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Aminopeptidase P (APPro) is a crucial metalloaminopeptidase involved in amino acid cleavage from peptide N-termini, playing essential roles as versatile biocatalysts with applications ranging from pharmaceuticals to industrial processes. Despite acknowledging its potential for catalysis in lower temperatures, detailed molecular basis and biotechnological implications in cold environments are yet to be explored. Therefore, this research aims to investigate the molecular mechanisms underlying the cold-adapted characteristics of APPro from Pseudomonas sp. strain AMS3 (AMS3-APPro) through a detailed analysis of its structure and dynamics. In this study, structure analysis and molecular dynamics (MD) simulation of a predicted model of AMS3-APPro has been performed at different temperatures to assess structural flexibility and thermostability across a temperature range of 0-60 °C over 100 ns. The MD simulation results revealed that the structure were able to remain stable at low temperatures. Increased temperatures present a potential threat to the overall stability of AMS3-APPro by disrupting the intricate hydrogen bond networks crucial for maintaining structural integrity, thereby increasing the likelihood of protein unfolding. While the metal binding site at the catalytic core exhibits resilience at higher temperatures, highlighting its local structural integrity, the overall enzyme structure undergoes fluctuations and potential denaturation. This extensive structural instability surpasses the localized stability observed at the metal binding site. Consequently, these assessments offer in-depth understanding of the cold-adapted characteristics of AMS3-APPro, highlighting its capability to uphold its native conformation and stability in low-temperature environments. In summary, this research provides valuable insights into the cold-adapted features of AMS3-APPro, suggesting its efficient operation in low thermal conditions, particularly relevant for potential biotechnological applications in cold environments.Communicated by Ramaswamy H. Sarma.

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A fetal pituitary hormone, oxytocin which causes uterine contractions, increases throughout gestation, and its increase reaches 10-fold from week 32 afterward. Oxytocin is, on the other hand, degraded by placental leucine aminopeptidase (P-LAP) which exists in both terminal villi and maternal blood. Maternal blood P-LAP increases with advancing gestation under the control of non-genomic effects of progesterone, which is also produced from the placenta. Progesterone is converted to estrogen by CYP17A1 localized in the fetal adrenal gland and placenta at term. The higher oxytocin concentrations in the fetus than in the mother demonstrate not only fetal oxytocin production but also its degradation and/or inhibition of leakage from fetus to mother by P-LAP. Until labor onset, the pregnant uterus is quiescent possibly due to the balance between increasing fetal oxytocin and P-LAP under control of progesterone. A close correlation exists between the feto-placental and maternal units in the placental circulation, although the blood in the two circulations does not necessarily mix. Fetal maturation results in progesterone withdrawal via the CYP17A1 activation accompanied with fetal oxytocin increase. Contribution of fetal oxytocin to labor onset has been acknowledged through the recognition that the effect of fetal oxytocin in the maternal blood is strictly regulated by its degradation by P-LAP under the control of non-genomic effects of progesterone. In all senses, the fetus necessarily takes the initiative in labor onset.

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A novel protein, PID-5, has been shown to be a requirement for germline immortality and has recently been implicated in RNA-induced epigenetic silencing in the Caenorhabditis elegans embryo. Importantly, it has been shown to contain both an eTudor and aminopeptidase P-related domain. However, the silencing mechanism has not yet been fully characterised. In this study, bioinformatic tools were used to compare pre-existing aminopeptidase P molecular structures to the AlphaFold2-predicted aminopeptidase P-related domain of PID-5 (PID-5 APP-RD). Structural homology, metal composition, inhibitor-bonding interactions, and the potential for dimerisation were critically assessed through computational techniques, including structural superimposition and protein-ligand docking. Results from this research suggest that the metallopeptidase-like domain shares high structural homology with known aminopeptidase P enzymes and possesses the canonical 'pita-bread fold'. However, the absence of conserved metal-coordinating residues indicates that only a single Zn2+ may be bound at the active site. The PID-5 APP-RD may form transient interactions with a known aminopeptidase P inhibitor and may therefore recognise substrates in a comparable way to the known structures. However, loss of key catalytic residues suggests the domain will be inactive. Further evidence suggests that heterodimerisation with C. elegans aminopeptidase P is feasible and therefore PID-5 is predicted to regulate proteolytic cleavage in the silencing pathway. PID-5 may interact with PID-2 to bring aminopeptidase P activity to the Z-granule, where it could influence WAGO-4 activity to ensure the balanced production of 22G-RNA signals for transgenerational silencing. Targeted experiments into APPs implicated in malaria and cancer are required in order to build upon the biological and therapeutic significance of this research.

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Aminopeptidases P are metalloproteases belonging to the M24 peptidase family. It specifically hydrolyzes the N-terminus of polypeptides free of acidic amino acids, and plays an important role in the nutrition, metabolism and growth of parasites. The aim of this study was to characterize a novel Trichinella spiralis aminopeptidase P (TsAPP) and to investigate its functions in the invasion of T. spiralis. TsAPP contained two domains of creatinase (a creatinase N and creatinase N2) and a domain of peptidase M24C and APP. The complete TsAPP sequence was cloned and expressed in Escherichia coli BL21 cells. The recombinantly produced TsAPP was used to raise polyclonal antibodies that were subsequently used to detect the expression of the protein in the different life stages of T. spiralis. TsAPP was expressed in various T. spiralis stages. TsAPP was primarily localized in the cuticle, stichosome and intrauterine embryos of this nematode. rTsAPP has an enzymatic activity of a natural aminopeptidase P to hydrolyze the substrate H-Ala-Pro-OH. rTsAPP promoted the larval intrusion of intestinal epithelium cells (IECs). The results showed that TsAPP is involved in the T. spiralis intrusion of IECs and it might be a potential candidate vaccine target against Trichinella infection.

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In pregnancy, placental circulation occurs through two independent circulation systems: foetoplacental and uterine (spiral artery)-placental lake. Crosstalk between the foetal peptide hormones, angiotensin II (A-II) and vasopressin (AVP), and their degrading placental aminopeptidases (APs), aminopeptidase A for A-II and placental leucine aminopeptidase for both AVP and oxytocin, primarily regulate placental circulation. On the other hand, placental circulation represents an arteriovenous shunt. In normal pregnancy, the blood pressure decreases, despite increased cardiac output and plasma volume, probably due to the arteriovenous shunt in the growing placenta. Actually, the foetal vasoactive hormones in the foetoplacental circulation are much higher than those in the maternal circulation throughout pregnancy. In normal pregnancy, AP activity derived from the placenta in maternal blood increases with gestation and placental growth. Foetal hypoxia increases the secretion of foetal both AVP and A-II. Although there is an increase in both AP activities in the maternal blood in normal pregnancy, their activities increase more than those in normal pregnancy during mild preeclampsia. However, both AP activities decline significantly compared than those in severe preeclampsia. This suggests that AP prevents leakage of increased foetal vasoactive hormones into the maternal blood in mild preeclampsia, and its protective role breaks down in severe preeclampsia, leading to a massive leak of the hormones into maternal circulation and consequent marked contraction of both the maternal vessels and the uterus. Consequently, AP activity in both placenta and maternal blood acts as the foeto-maternal barrier for foetal vasoactive hormones and thus contributes to the onset of preeclampsia.

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Oxytocin and oxytocin receptors are synthesized in the periphery where paracrine/autocrine actions have been described alongside endocrine actions effected by central release of oxytocin from the posterior pituitary. In the female reproductive system, classical actions of uterine contraction and milk ejection from mammary glands are accompanied by actions in the ovaries where roles in steroidogenesis, follicle recruitment and ovulation have been described. Steroidogenesis, contractile activity, and gamete health are similarly affected by oxytocin in the male reproductive tract. In the cardiovascular system, a local oxytocinergic system appears to play an important cardio-protective role. This role is likely associated with emerging evidence that peripheral oxytocin is an important hormone in the endocrinology of glucose homeostasis due to its actions in adipose, the pancreas, and the largely ignored oxytocinergic systems of the adrenal glands and liver. Gene polymorphisms are shown to be associated with a number of reported traits, not least factors associated with metabolic syndrome.

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Trichinella spiralis is a major foodborne zoonotic parasitic nematode which has a serious threat to meat food safety. Development of anti-Trichinella vaccine is requisite for control and elimination of Trichinella infection in food animals to ensure meat safety. Aminopeptidase P (TsAPP) and cathepsin X (TsCX) are two novel proteins identified in T. spiralis intestinal infectious L1 larvae (IIL1). The objective of this study was to investigate the protective immunity elicited by immunization with TsAPP and TsCX alone and TsAPP-TsCX in combination in a mouse model. The results demonstrate that subcutaneous vaccination of mice with rTsAPP, rTsCX or rTsAPP + rTsCX elicited a systemic humoral response (high levels of serum IgG, IgG1/IgG2a and IgA) and significant local gut mucosal sIgA responses. The vaccination with rTsAPP, rTsCX or rTsAPP + rTsCX also induced a systemic and local mixed Th1/Th2 response, as demonstrated by clear elevation levels of IFN-γ and IL-4 in vaccinated mice. Vaccination of mice with rTsAPP+rTsCX exhibited a 63.99 % reduction of intestinal adult worms and 68.50% reduction of muscle larva burdens, alleviated inflammation of intestinal mucosal and muscle tissues, and provided a higher immune protection than that of vaccination with rTsAPP or rTsCX alone. The results demonstrated that TsAPP and TsCX might be considered novel candidate target molecules for anti-Trichinella vaccines.

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Cisplatin is a highly effective chemotherapeutic agent. However, its use is limited by nephrotoxicity. Enalapril is an angiotensin I-converting enzyme inhibitor used for the treatment of hypertension, mainly through the reduction of angiotensin II formation, but also through the increase of kinins half-life. Kinin B1 receptor is associated with inflammation and migration of immune cells into the injured tissue. We have previously shown that the deletion or blockage of kinin B1 and B2 receptors can attenuate cisplatin nephrotoxicity. In this study, we tested enalapril treatment as a tool to prevent cisplatin nephrotoxicity. Male C57Bl/6 mice were divided into 3 groups: control group; cisplatin (20 mg/kg i.p) group; and enalapril (1.5 mg;kg i.p) + cisplatin group. The animals were treated with a single dose of cisplatin and euthanized after 96 h. Enalapril was able to attenuate cisplatin-induced increase in creatinine and urea, and to reduce tubular injury and upregulation of apoptosis-related genes, as well as inflammatory cytokines in circulation and kidney. The upregulation of B1 receptor was blocked in enalapril + cisplatin group. Carboxypeptidase M expression, which generates B1 receptor agonists, is blunted by cisplatin + enalapril treatment. The activity of aminopeptidase P, a secondary key enzyme able to degrade kinins, is restored by enalapril treatment. These findings were confirmed in mouse renal epithelial tubular cells, in which enalaprilat (5 µM) was capable of decreasing tubular injury and inflammatory markers. We treated mouse renal epithelial tubular cells with cisplatin (100 µM), cisplatin+enalaprilat and cisplatin+enalaprilat+apstatin (10 µM). The results showed that cisplatin alone decreases cell viability, cisplatin plus enalaprilat is able to restore cell viability, and cisplatin plus enalaprilat and apstatin decreases cell viability. In the present study, we demonstrated that enalapril prevents cisplatin nephrotoxicity mainly by preventing the upregulation of B1 receptor and carboxypeptidase M and the increased concentrations of kinin peptides through aminopeptidase activity restoration.

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BACKGROUND: Proline specific peptidases (PSPs) are a unique group of enzymes that specifically cleave bonds formed by a proline residue. The study of PSPs is important due to their role in the maturation and degradation of peptide hormones and neuropeptides. In addition, changes in the activity of PSPs can result in pathological conditions, including various types of cancer. SCOPE OF REVIEW: PSPs annotated from the Homo sapiens genome were compared and classified by their physicochemical and biochemical features and roles in vital processes. In addition to catalytic activity, we discuss non-enzymatic functions that may regulate cellular activity. MAJOR CONCLUSIONS: PSPs apparently have multiple functions in animals. Two functions rely on the catalytic activity of the enzyme: one involved in a regulatory pathway associated with the ability of many PSPs to hydrolyze peptide hormones and neuropeptides, and the other involved in the trophic pathway associated with the proteolysis of total cellular protein or Pro-containing dietary proteins in the digestive tract. PSPs also participate in signal transduction without proteolytic activity by forming protein-protein interactions that trigger or facilitate the performance of certain functions. GENERAL SIGNIFICANCE: PSPs are underestimated as a unique component of the normal human peptidase degradome, providing the body with free proline. A comparative analysis of PSPs can guide research to develop inhibitors that counteract the abnormalities associated with changes in PSP activity, and identify natural substrates of PSPs that will enable better understanding of the mechanisms of the action of PSPs in biological processes and disease.

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M24B peptidases cleaving Xaa-Pro bond in dipeptides are prolidases whereas those cleaving this bond in longer peptides are aminopeptidases-P. Bacteria have small aminopeptidases-P (36-39 kDa), which are diverged from canonical aminopeptidase-P of Escherichia coli (50 kDa). Structure-function studies of small aminopeptidases-P are lacking. We report crystal structures of small aminopeptidases-P from E. coli and Deinococcus radiodurans, and report substrate-specificities of these proteins and their ortholog from Mycobacterium tuberculosis. These are aminopeptidases-P, structurally close to small prolidases except for absence of dipeptide-selectivity loop. We noticed absence of this loop and conserved arginine in canonical archaeal prolidase (Maher et al., Biochemistry. 43, 2004, 2771-2783) and questioned its classification. Our enzymatic assays show that this enzyme is an aminopeptidase-P. Further, our mutagenesis studies illuminate importance of DXRY sequence motif in bacterial small aminopeptidases-P and suggest common evolutionary origin with human XPNPEP1/XPNPEP2. Our analyses reveal sequence/structural features distinguishing small aminopeptidases-P from other M24B peptidases.

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Previously, metalloproteinase was isolated and identified from Trichomonas vaginalis, belonging to the aminopeptidase P-like metalloproteinase subfamily A/B, family M24 of clan MG, named TvMP50. The native and recombinant TvMP50 showed proteolytic activity, determined by gelatin zymogram, and a 50 kDa band, suggesting that TvMP50 is a monomeric active enzyme. This was an unexpected finding since other Xaa-Pro aminopeptidases/prolidases are active as a biological unit formed by dimers/tetramers. In this study, the evolutionary history of TvMP50 and the preliminary crystal structure of the recombinant enzyme determined at 3.4 Å resolution is reported. TvMP50 was shown to be a type of putative, eukaryotic, monomeric aminopeptidase P, and the crystallographic coordinates showed a monomer on a "pseudo-homodimer" array on the asymmetric unit that resembles the quaternary structure of the M24B dimeric family and suggests a homodimeric aminopeptidase P-like enzyme as a likely ancestor. Interestingly, TvMP50 had a modified N-terminal region compared with other Xaa-Pro aminopeptidases/prolidases with three-dimensional structures; however, the formation of the standard dimer is structurally unstable in aqueous solution, and a comparably reduced number of hydrogen bridges and lack of saline bridges were found between subunits A/B, which could explain why TvMP50 portrays monomeric functionality. Additionally, we found that the Parabasalia group contains two protein lineages with a "pita bread" fold; the ancestral monomeric group 1 was probably derived from an ancestral dimeric aminopeptidase P-type enzyme, and group 2 has a probable dimeric kind of ancestral eukaryotic prolidase lineage. The implications of such hypotheses are also presented.

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On a pathophysiological level, angioedema can be differentiated into histamine- and bradykinin-mediated types. The prototype drug-associated, bradykinin-mediated form of angioedema is angiotensin-converting enzyme (ACE) inhibitor-induced angioedema. The hypothesized cause is a decrease in bradykinin degradation via ACE inhibition. In this scenario, other bradykinin-degrading enzymes assume major importance. When the effect of these enzymes is also diminished, e. g., due to genetic variants or external factors, compensation for the inhibition of ACE may be insufficient. An increased risk of angioedema has also been reported for other drugs, particularly when prescribed in combination with ACE inhibitors. Here, the suspected cause also relates to the degradation of bradykinin. When angioedema arises within the context of concomitant ACE inhibitor use, additive bradykinin degradation effects may be implicated.

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Metabolic diseases affect various organs including the brain. Accumulation or depletion of substrates frequently leads to brain injury and dysfunction. Deficiency of aminopeptidase P1, a cytosolic proline-specific peptidase encoded by the Xpnpep1 gene, causes an inborn error of metabolism (IEM) characterized by peptiduria in humans. We previously reported that knockout of aminopeptidase P1 in mice causes neurodevelopmental disorders and peptiduria. However, little is known about the pathophysiological role of aminopeptidase P1 in the brain. Here, we show that loss of aminopeptidase P1 causes behavioral and neurological deficits in mice. Mice deficient in aminopeptidase P1 (Xpnpep1-/- ) display abnormally enhanced locomotor activities in both the home cage and open-field box. The aminopeptidase P1 deficiency in mice also resulted in severe impairments in novel-object recognition, the Morris water maze task, and contextual, but not cued, fear memory. These behavioral dysfunctions were accompanied by epileptiform electroencephalogram activity and neurodegeneration in the hippocampus. However, mice with a heterozygous mutation for aminopeptidase P1 (Xpnpep1+/- ) exhibited normal behaviors and brain structure. These results suggest that loss of aminopeptidase P1 leads to behavioral, cognitive and neurological deficits. This study may provide insight into new pathogenic mechanisms for brain dysfunction related to IEMs.

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PepP is a virulence-associated gene in Pseudomonas aeruginosa, making it an attractive target for anti-P. aeruginosa drug development. The encoded protein, aminopeptidases P (Pa-PepP), is a type of X-prolyl peptidase that possesses diverse biological functions. The crystal structure verified its canonical pita-bread fold and functional tetrameric assembly, and the functional studies measured the influences of different metal ions on the activity. A trimetal manganese cluster was observed at the active site, elucidating the mechanism of inhibition by metal ions. Additionally, a loop extending from the active site appeared to be important for specific large-substrate binding. Based on the structural comparison and bacterial invasion assays, we showed that this non-conserved surface loop was critical for P. aeruginosa virulence. Taken together, these findings can extend our understanding of the catalytic mechanism and virulence-related functions of Pa-PepP and provide a solid foundation for the design of specific inhibitors against pathogenic-bacterial infections.

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Hyperactivity of the renin-angiotensin system (RAS) is associated with the pathogenesis of Alzheimer's disease (AD) believed to be mediated by angiotensin-II (Ang-II) activation of the angiotensin type 1 receptor (AT1R). We previously showed that angiotensin-converting enzyme-1 (ACE-1) activity, the rate-limiting enzyme in the production of Ang-II, is increased in human postmortem brain tissue in AD. Angiotensin-III (Ang-III) activates the AT1R and angiotensin type-2 receptor (AT2R), but its potential role in the pathophysiology of AD remains unexplored. We measured Ang-II and Ang-III levels by ELISA, and the levels and activities of aminopeptidase-A (AP-A) and aminopeptidase-N (AP-N) (responsible for the production and metabolism of Ang-III, respectively) in human postmortem brain tissue in the mid-frontal cortex (Brodmann area 9) in a cohort of AD (n = 90) and age-matched non-demented controls (n = 59), for which we had previous measurements of ACE-1 activity, Aß level, and tau pathology (also in the mid-frontal cortex). We found that both Ang-II and Ang-III levels were significantly higher in AD compared to age-matched controls and that Ang-III, rather than Ang-II, was strongly associated with Aß load and tau load. Levels of AP-A were significantly reduced in AD but AP-A enzyme activity was unchanged whereas AP-N activity was reduced in AD but AP-N protein level was unchanged. Together, these data indicate that the APA/Ang-III/APN/Ang-IV/AT4R pathway is dysregulated and that elevated Ang-III could contribute to the pathogenesis of AD.

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Eukaryotic aminopeptidase P1 (APP1), also known as X-prolyl aminopeptidase (XPNPEP1) in human tissues, is a cytosolic exopeptidase that preferentially removes amino acids from the N-terminus of peptides possessing a penultimate N-terminal proline residue. The enzyme has an important role in the catabolism of proline containing peptides since peptide bonds adjacent to the imino acid proline are resistant to cleavage by most peptidases. We show that recombinant and catalytically active Caenorhabditis elegans APP-1 is a dimer that uses dinuclear zinc at the active site and, for the first time, we provide structural information for a eukaryotic APP-1 in complex with the inhibitor, apstatin. Our analysis reveals that C. elegans APP-1 shares similar mode of substrate binding and a common catalytic mechanism with other known X-prolyl aminopeptidases.

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Tumor necrosis factor (TNF) is an important mediator that triggers onset of autoimmune diseases and exerts its biological effects by interacting through two receptors, TNFR1 (also known as TNFRSF1A) and TNFR2 (also known as TNFRSF1B). TNFR2 signaling has significant potential to exert pro-survival and protective roles in several diseases. Unlike TNFR1 signaling, however, the mechanism of TNFR2 signal transduction is poorly understood, and few of its adaptor molecules are known. The present study utilized a proteomics approach to search for adaptor molecules in the TNFR2 signaling complex and identified aminopeptidase P3 (APP3, also known as XPNPEP3) to be a key molecule. One of its two isoforms, mitochondrial APP3 (APP3m) but not cytosolic APP3 (APP3c), was recruited to TNFR2 and shown to regulate TNF-TNFR2-dependent phosphorylation of JNK1 (also known as MAPK8) and JNK2 (also known as MAPK9). Furthermore, APP3m was released from mitochondria upon TNF stimulation in the absence of mitochondrial outer membrane permeabilization (MOMP). The observation of increased cell death upon downregulation of APP3m also suggested that APP3m exerts an anti-apoptotic function. These findings reveal that APP3m is a new member of the TNF-TNFR2 signaling complex and characterize an APP3-mediated TNFR2 signal transduction mechanism that induces activation of JNK1 and JNK2.

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Presence of proline residues in the second position of the N-terminus in peptides restricts the usage of many aminopeptidases; however, aminopeptidase P (APP) is capable of removing this blockage. Based on the N-terminal amino acid sequences of APP from Streptomyces lavendulae, app gene was cloned in pET28a(+) and over expressed as a His-tagged protein with a molecular weight of ≈60 kDa in Escherichia coli BL21 (DE3). Nucleotide sequencing revealed a 1467 bp open reading frame encoding 488 amino acids (NCBI Accession No: GenBank: KC292272.1). The substrate specificity of the recombinant APP was analyzed by the hydrolysis of the Xaa-Pro bond in Gly-Pro dipeptide and bradykinin. K(m) and V(max) of the enzyme were found to be 0.4697 mmol l⁻¹ and 0.6396 µmol min⁻¹, respectively. APP activity was enhanced in the presence of metal ions such as Co²âº, Mn²âº, Mg²âº and Cu²âº ions and was inhibited by 1,10-phenanthroline, EDTA, PMSF and DTT. The atomic absorption studies revealed the presence of Mn²âº in the protein as a co-factor. This substrate specific metalloenzyme was found to be a tetramer and optimally active at pH 8 and 37 °C.

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BACKGROUND: Angioedema (AE) is idiopathic in the majority of cases. We studied patients with AE for genetic variants of proteins involved with bradykinin generation and biodisposition. METHODS: One hundred sixty one patients with AE were recruited at a university hospital clinic. Patients were categorized according to the proposed pathogenesis of AE: low C1 inhibitor (C1-INH) and C4 levels, autoimmune disease, cancer, angiotensin-converting enzyme (ACE) inhibitor-induced, nonsteroidal antiinflammatory drug (NSAID)-induced, or idiopathic. In addition, each patient had a blood sample analyzed for a complement profile and enzymes (C1-INH and C4). Fifty-two of the patients were tested for genetic variants in factor XII, plasminogen-activator inhibitor-1 (PAI-1), ACE, and aminopeptidase P (APP). RESULTS: The cause of angioedema was identified in 59/161 (37%) of the cases: 3 (2%) patients had a low plasma C1-INH and C4; 20 (12%) were ACE inhibitor-induced; 12 (7%) were associated with autoimmune disorders; 7 (4%) were associated with malignancy; and 17 (11%) were associated with NSAIDs. In the remaining 102 (63%) patients the cause of angioedema was idiopathic. Of 52 patients with genetic analysis, 13 (25%) had a genetic variant in APP, 10 (19%) in ACE, 13 (25%) in PAI-1, and 0 in Factor XII. CONCLUSIONS: In addition to related diseases and medications causing AE, certain genetic variants encoding proteins involved in bradykinin generation and/or catabolism pathways may be involved in the pathogenesis of AE.