What’s new in the renin-angiotensin system?

Angiotensin-converting enzyme 2 (ACE2) is a recently discovered homologue of the key enzyme of the renin-angiotensin system, the angiotensin-converting enzyme. The ACE2 enzyme is mainly expressed in cardiac blood vessels and tubular epithelia of the kidneys. Together with ACE2's unique metallocarboxypeptidase activity, the restricted tissue distribution suggests a distinctive physiological function in blood pressure, blood flow and fluid regulation. The ace2 gene was mapped to quantitative trait loci affecting susceptibility to hypertension in rats. Furthermore, ACE2 appears to be a negative regulator of ACE in the heart. ACE2 messenger RNA and protein levels are substantially regulated in the kidney of diabetic and pregnant rats. The mechanism of ACE2 function and its physiologic significance are not yet fully understood; however, as ACE2 differs in its specificity and physiological role from ACE, this opens a new potential venue for drug discovery aimed at cardiovascular disease, hypertension and diabetic complications.     

Gametes contain angiotensin converting enzyme (kininase II)

The localization of angiotensin converting enzyme (ACE) in the gonads of the normal rabbit was studied by immunofluorescence and immunoelectron microscopy. The enzyme is present in the cytoplasm of testicular spermatids and of epididymal and ejaculated spermatozoa, and on the surface of follicular and tubal oocytes. These findings support the hypothesis that ACE has a role in gamete maturation and in fertilization.     

Not just angiotensinases: new roles for the angiotensin-converting enzymes

The renin-angiotensin system (RAS) is a critical regulator of blood pressure and fluid homeostasis. Angiotensin II, the primary bioactive peptide of the RAS, is generated from angiotensin I by angiotensin-converting enzyme (ACE). A homologue of ACE, ACE2, is able to convert angiotensin II to a peptide with opposing effects, angiotensin-(1-7). It is proposed that disturbance of the balance of ACE and ACE2 expression and/or function is important in pathologies in which angiotensin II plays a role. These include cardiovascular and renal disease, lung injury and liver fibrosis. The critical roles of ACE and ACE2 in regulating angiotensin II levels have traditionally focussed attention on their activities as angiotensinases. Recent discoveries, however, have illuminated the roles of these enzymes and of the ACE2 homologue, collectrin, in intracellular trafficking and signalling. This paper reviews the key literature regarding both the catalytic and non-catalytic roles of the angiotensin-converting enzyme gene family.     

What’s new in the renin-angiotensin system?

Angiotensin-converting enzyme (ACE) is a zinc- and chloride-dependent metallopeptidase that plays a vital role in the metabolism of biologically active peptides. Until recently, much of the inhibitor design and mechanism of action of this ubiquitous enzyme was based on the structures of carboxypeptidase A and thermolysin. When compared to the recently solved structures of the testis isoform of ACE (tACE) and its Drosophila homologue (AnCE), carboxypeptidase A showed little structural homology outside of the active site, while thermolysin revealed significant but less marked overall similarity. The ellipsoid-shaped structure of tACE, which has a preponderance of -helices, is characterised by a core channel that has a constriction approximately 10 Å from its opening where the zinc-binding active site is located. Comparison of the native protein with the inhibitor-bound form (lisinopril-tACE) does not reveal any striking differences in the conformation of the inhibitor binding site, disfavouring an open and closed configuration. However, the inhibitor complex does provide insights into the network of hydrogen-bonding and ionic interactions in the active site as well as the mechanism of ACE substrate hydrolysis. The three-dimensional structure of ACE now paves the way for the rational design of a new generation of domain-selective ACE inhibitors.     

Angiotensin-converting enzyme 2 in acute respiratory distress syndrome

Angiotensin-converting enzyme (ACE) and ACE2 are highly homologous metalloproteases that provide essential catalytic functions in the renin-angiotensin system (RAS). Angiotensin II is one key effector peptide of the RAS, inducing vasoconstriction and exerting multiple biological functions. ACE cleaves angiotensin I to generate angiotensin II, whereas ACE2 reduces angiotensin II levels. Accumulating evidence has demonstrated a physiological and pathological role of ACE2 in the cardiovascular systems. Intriguingly, the SARS coronavirus, the cause of severe acute respiratory syndrome (SARS), utilizes ACE2 as an essential receptor for cell fusion and in vivo infections. Moreover, recent studies have demonstrated that ACE2 protects murine lungs from acute lung injury as well as SARS-Spike protein-mediated lung injury, suggesting a dual role of ACE2 in SARS infections and protection from ARDS. Received 18 May 2006; received after revision 12 March 2007; accepted 24 April 2007     

Cyclosporine resistant effector cells in rabbit skin allografts

Summary Histoincompatible skin grafts in rabbits treated with cyclosporine can permanently engraft but show a transient mononuclear cellular infiltrate. This transient cyclosporine-resistant infiltrate consists of cells which are sensitive to steroids, radiation and cryopreservation. They have the same ACM-1 phenotype and the same characteristics as cyclosporine-sensitive cells.9 January 1987Supported by the Swiss National Research Foundation, Grant No. 3.908-0.83.     

Effect of fluoride administration on renal glucose-6-phosphatase activity in rats

Summary Renal glucose-6-phosphatase activity was found to be significantly elevated by fluoride administration (NaF 35 mg/kg, i.p.). The elevation of the enzyme activity was markedly suppressed by adrenalectomy.This work was supported in part by the Scientific Research Foundation (Grant 7014-267337) from the Education and Culture Ministry of Japan.     

Depletion of angiotensin-converting enzyme 2 reduces brain serotonin and impairs the running-induced neurogenic response

Physical exercise induces cell proliferation in the adult hippocampus in rodents. Serotonin (5-HT) and angiotensin (Ang) II are important mediators of the pro-mitotic effect of physical activity. Here, we examine precursor cells in the adult brain of mice lacking angiotensin-converting enzyme (ACE) 2, and explore the effect of an acute running stimulus on neurogenesis. ACE2 metabolizes Ang II to Ang-(1–7) and is essential for the intestinal uptake of tryptophan (Trp), the 5-HT precursor. In ACE2-deficient mice, we observed a decrease in brain 5-HT levels and no increase in the number of BrdU-positive cells following exercise. Targeting the Ang II/AT1 axis by blocking the receptor, or experimentally increasing Trp/5-HT levels in the brain of ACE2-deficient mice, did not rescue the running-induced effect. Furthermore, mice lacking the Ang-(1–7) receptor, Mas, presented a normal neurogenic response to exercise. Our results identify ACE2 as a novel factor required for exercise-dependent modulation of adult neurogenesis and essential for 5-HT metabolism.     

Effect of trypsin,S-adenosylmethionine and ethionine on L-serine sulfhydrase activity

Summary Trypsin causes an activation of serine sulfhydrase in the liver extracts from intact animals, but inhibits enzyme activity in the liver of ethionine treated rats. Trypsin also decreases an elevation of serine sulfhydrase activity caused by S-adenosylmethionine.This work was supported by the Serbian Medical Research Foundation.     

Unusually strong lipophilicity of ‘fat’ or ‘super’ amino-acids,including a new reference value for glycine

Summary Lipophilic, steric, electronic, and enzyme resistance characteristics of carboranylalanine, adamantylalanine, neopentylglycine and tert-butylglycine are described. The first 2 amino-acids display lipophilicities 2 orders of magnitude higher than tryptophan.This work was supported by research grants to Prof. R. Schwyzer from the Swiss National Science Foundation.     

The membrane attack complex ofXeopus laevis complement

Summary Rabbit erythrocyte membranes lyzed byXenopus laevis serum exhibited a typical ultrastructural complement lesion with an inner diameter of 80±9Å. The protein pattern associated with lyzed membrane is compared to a similar human preparation.Acknowledgments. I wish to thank Dr. I. Hadji-Azimi for her interest and encouragement, and Professor N. Parrinello for critical reading. This work was supported by a grant from the Swiss National Science Foundation (3.083–0.84).     

What’s new in the renin-angiotensin system?

Cellular entry of enveloped viruses is often dependent on attachment proteins expressed on the host cell surface. Viral envelope proteins bind these receptors, and, in an incompletely understood process, facilitate fusion of the cellular and viral membranes so as to introduce the viral core into the cytoplasm. Only a small fraction of viral receptors have been identified so far. Recently, a novel coronavirus was identified as the etiological agent of severe acute respiratory syndrome (SARS). The fusion protein gene of SARS coronavirus (SARS-CoV) was cloned and characterized, and shortly thereafter, angiotensin-converting enzyme 2 (ACE2) was shown to be its functional receptor. Identification of ACE2 as a receptor for SARS-CoV will likely contribute to the development of antivirals and vaccines. It may also contribute to the development of additional animal models for studying SARS pathogenesis, and could help identify the animal reservoir of SARS-CoV.     

Studies on the hydrolysis of bradykinin by angiotensin-converting enzyme (kininase II)

Summary Arg-Pro-Pro-Gly-Phe, the N-terminal pentapeptide of bradykinin, is not an inhibitor of angiotensin-converting enzyme and is not hydrolyzed by the enzyme. Arg-Pro-Pro, the N-terminal tripeptide is a relatively potent (IC₅₀=2.3×10⁶ M) inhibitor but its higher homolog, Gly-Arg-Met-Lys-Arg-Pro-Pro is not an inhibitor of angiotensin-converting enzyme.This work was supported in part by grants from the US Public Health Service (HL 18415, HL 15691, HL 19764) and the John A. Hartford Foundation, Inc., and by the Medical Research Service of the Veterans Administration.     

Effect of nerve stimulation,denervation, and duct ligation,on kallikrein content and duct cell granules of the cat's submandibular gland

Summary Various procedures which reduce or deplete the kallikrein content of the cat's submandibular gland correspondingly reduce the number of apical granules in the striated duct cells. The kallikrein content is greatly reduced after chronic parasympathetic but not after sympathetic nerve section which suggests that the parasympathetic innervation is required for synthesis or storage of this enzyme.We wish to acknowledge the valuable assistance of Dr T. Nihei and Mr. J. Wimal in some of the enzyme measurements.This work was supported by grants from the Medical Research Council of Canada and the Alberta Heart Foundation.     

Manipulating the activity of immobilized enzymes with different organo-smectite complexes

Summary Enzymes may be immobilized on hydrophobic surfaces of organo-smectite complexes. The immobilized enzyme may be active, partially active, or inactive depending on the nature of the organic surface. These materials may be useful as models for enzymes in natural systems, and in medicine and industry.This work was partially supported by the National Science Foundation under Grant No. CHE-8306583. Journal Article No. 11603 of the Michigan Agricultural Experiment Station.     

Effect of botulinum toxin on the choline acetyltransferase activity in salivary glands of cats

Summary The choline acetyltransferase activity of submandibular glands that had previously received a retrograde injection of botulinum toxin via their ducts was found to be markedly lower than in the untreated contralateral glands. In the parotid glands exposed to the same treatment the activity of this enzyme was less affected.This work was supported by grants from the Wellcome Foundation to S. K. K. and J. R. G., and from the Faculty of Medicine in Lund to J. E.     

The reported occurrence of L-canavanine in soya bean,Glycine max

Summary The reported occurrence of L-canavanine in soya bean,Glycine max could not be verified by enzyme treatment of the extracted non-protein amino acids of the seed.This work was supported by a grant from the National Science Foundation (BMS-75-19770) and funds from N.I.H. Biomedical Grant 5-SO5-RR07114-08.The author thanks Dr D. B. Egli of the University of Kentucky for soya bean seeds and Karen Hughes for her technical assistance.     

An alkaline protease in the delayed hypersensitivity skin lesions in the guinea-pigs

Summary An alkaline hemoglobinolytic protease was extracted from the delayed hypersensitivity skin lesions induced by bovine -globulin as an antigen in the guinea-pig. The enzyme was heat-labile and inhibited by thiol-blocking reagents. The mol.wt was more than 100,000 and optimal pH around 9.We thank Prof. Hideo Hayashi and Yoshimasa Morino, Kumamoto University, for valuable discussions. This work was supported in part by grants from the Ministry of Education in Japan, the Naito Research Grant. Tokyo, and the Mitsukoshi Foundation, Tokyo.     

Evidence of a pollen esterase capable of hydrolyzing sporopollenin

Summary The activity of an esterase is associated with the germinal pore formation of the pollen grains of barley. Cytochemical evidence is given that the enzyme is capable of hydrolyzing sporopollenin. Some staining methods new to palynological studies were introduced.Dr.J. R. Rowley is thanked for suggestions to the MS. The work was supported by the Finnish Academy and by a grant from the Eemil Aaltosen Säätiö Foundation, and from the Finnish Academy of Science.     

Subcellular location of glycolytic enzymes inTrypanosoma brucei culture form

Summary The presence of a glycolytic complex or particle has been demonstrated in the insect midgut form ofTrypanosoma brucei brucei. It differs from the ‘glycosome’ of the bloodstream form of the parasite in that 3-phosphoglycerate kinase is absent. The latter enzyme appears to be cytosolic. Acknowledgment. We are grateful to Dr R. Brun for the kind supply of the strain. The work was funded by the Swiss National Science Foundation No. 3.331.0.78.