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(The FASEB Journal. 2006;20:1034-1038.)
© 2006 FASEB

The ACE and I: how ACE inhibitors came to be

Ervin G. Erdös1

Chicago Laboratory of Peptide Research, Department of Pharmacology, University of Illinois, Chicago, Illinois, USA

1Correspondence: University of Illinois, Chicago Laboratory of Peptide Research Department of Pharmacology (MC 868) 835 S. Wolcott, Rm. E403, Chicago, IL 60612, USA. E-mail: egerdos{at}uic.edu

THE BEGINNING

The origins of the renin-angiotensin system (RAS) and the kallikrein-kinin system (KKS) can be traced back to the 19th century. Tigerstedt and Bergman’s article on renin was published in 1898 (1) , and the biological (toxic) actions of urine in 1889 (2) . Subsequently, Abelous and Bardier in 1909 and Petroff in 1925 reported the hypotensive effect of extracts from urine or pancreas (3) . In 1926, Frey and Kraut (4) described a substance in urine that was later called kallikrein. Next came the finding that neither kallikrein nor renin was vasoactive per se, but both of these substances released mediators from blood plasma, discovered first for kallikrein and later for renin (5 , 6) . The discovery of angiotonin and hypertensin (now called angiotensin, Ang) was described about the same time in 1939 (5) .

Earlier (1937), Werle disclosed that kallikrein released a labile vasoactive peptide from plasma protein. This peptide was identified as kallidin (Lys1-bradykinin) (6 , 7) very shortly before Beraldo and Rocha e Silva showed that trypsin releases bradykinin (BK) (8) . Skeggs and colleagues reported in 1954–1956 that renin liberates a decapeptide Ang I, which is converted by a factor in horse plasma, to the active peptide to Ang II in presence of Cl–. They named this factor angiotensin converting enzyme (ACE) (9 , 10) . John Vane and associates noted the importance of the pulmonary circulation for conversion of Ang I and inactivation of BK, although they attributed these actions to a different enzyme, carboxypeptidase N (11 , 12) . (I informed Vane that Ang I conversion was due to ACE, a fact that he later acknowledged publicly.)

Initially, two groups of investigators worked separately and independently on the RAS and KKS, possibly unaware of developments in the parallel field. The connection was first made in my laboratory at the University of Oklahoma in collaboration with H. Y. T. Yang and Y. Levin of the Weizmann Institute, when we discovered that the ACE and the kininase II we had described previously (13 14 15 16) are identical. The same protein, acting as a peptidyl-dipeptidase, releases the C-terminal dipeptide His9-Leu10 from Ang I to form the vasoconstrictor Ang II, and releases the C-terminal Phe8-Arg9 from BK ( Fig. 1 ). We first named the enzyme dipeptidyl carboxypeptidase and even though the name is incorrect, it still prevails. We confirmed our findings with a purified lung protein, which yielded a single band on electrophoresis and had the same dual actions (17) . Next, experiments with short synthetic peptide substrates indicated an identical enzyme in plasma, lung and kidney (18) .


Figure 1
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  		Figure 1. Actions of ACE, Kininase II.

The idea that ACE is kininase II was not easily accepted. The inactivation of bradykinin and the activation of Ang II were repeatedly attributed to two different enzymes (12 , 19) . Other investigators maintained that the cleavage of Ang I was highly Cl– dependent (9 , 10) , while we found that BK inactivation was not (20) . We had our own bias. We thought that our kininase II, the one we discovered in 1967 (13 , 14) , could not and would not be identical with Skegg’s ACE, but our own experiments showed otherwise. Finding two active domains with different Cl– sensitivities and substrate and inhibitor affinities in human ACE helped to clarify these issues (21 , 22) . The reported Km values range around 16 µM for Ang I and less than 1 µM for BK (21 , 23 , 24) . Consequently, a single protein molecule (ACE or kininase II) links the renin and kallikrein systems, which heretofore were thought to release independently vasoactive mediators.

Later, we found out that our beloved enzyme exhibited some strange behavior. It was not only promiscuous, cleaving a variety of different peptides at the C terminus, but it had what Irvine Page (5) called "bisexual behavior," because it also attacked N-termini (24) . (This sort of thing happens when one works with enzymes too long and finally anthropomorphizes them.)

ACE INHIBITION

After ACE was characterized, it became fairly obvious that its inhibitors would have dual—hopefully beneficial—effects. The trickle of early papers on RAS and KKS and their inhibitors burgeoned into a diluvium of publications: 43,700 abstracts were published within the last five years on their components. This volume of information is unsurveyable and incomprehensible and as a challenge, insurmountable.

How did I get into all of that, into peptide metabolism? I worked with Werle in Munich, finding kinins in urine, then later in Pittsburgh on cholinesterases that cleaved acetylcholine (ACh) and related esters (25) . After BK was synthesized (26) , I started studying peptide metabolism. Thus, I switched from ACh to ACE, but that one letter substitution took decades (25) . Our aims were expressed in a review on hypotensive peptides, which in 1966 had already 600 references (27) . Although investigators at that time sought to find substances that lower elevated blood pressure, I suggested that "if kinins play a significant role ... agents which block their effects or inhibit their enzymatic metabolism would be of prime importance." This concept was derived from working with cholinesterases and muscarinic or nicotinic receptors.

The first kininase we found was carboxypeptidase N of human plasma, that cleaved the C-terminal Arg9 of BK, as reported at the First Pharmacology Congress in 1961 in Stockholm (28) . Because it was a metalloenzyme with zinc cofactor, Rocha e Silva and Ferreira in 1962 used the BAL (dimercaptopropanol) to potentiate BK effects by inhibiting its degradation (29) . Werle and associates, however, already disclosed in 1937–1939 that cysteine enhanced the effect of KKS (3 , 4) . Binding the enzyme cofactor with various compounds increased the hypotensive action BK in guinea pigs. Of the eight inhibitors of kinin inactivation, six had SH groups (30) . We realized only later the augmented hypotension could be due to inhibition of ACE or kininase II, rather than carboxypeptidase N. ACE is also a metallopeptidase, and the guinea pig had the highest plasma ACE levels of all the animals we tried (16) .

The term "kininase II" was born when H. Y. T. Yang and I detected an enzyme in a Clostridium histolyticum extract, then in the kidney and in human plasma that releases the Phe8-Arg9 from BK instead of the single Arg9, as carboxypeptidase N. Without overstressing our intellectual capacities, we named this second enzyme, which inactivated BK by liberating a dipeptide, "kininase II." Carboxypeptidase N thus became kininase I (13 14 15 16 , 21 , 25) .

In the sixties, Sergio Ferreira, an associate of Rocha e Silva, joined Vane in London. He found that a substance from the venom of Bothrops jararaca potentiated BK on smooth muscles and also blocked inactivation of BK (31) . The first inhibitor isolated from the venom was a pentapeptide (BPP5) (32) , a slow substrate of ACE (16) . Purification and synthesis of a nonapeptide (BPP9, teprotide) with an ACE-resistant Pro-Pro C terminus (33) soon followed. Japanese investigators purified a similar inhibitor peptide from the venom of another snake, Agkistrodon halys Blomhoffi (34) . The BK potentiating peptide brought by Ferreira to London traveled back to the Western hemisphere when Vane persuaded his old friend and mentor, A. D. Welch, to investigate its potential usefulness in clinical medicine as an ACE inhibitor (35 36 37 38) . Welch, president of Squibb Company’s research institute, initiated research with David Cushman, a biochemist, and Miguel Ondetti, an organic chemist, who later received the Lasker Award for their work on inhibition of ACE. Zola Horovitz and Charles Smith, associates of Dr. Welch, were involved in ACE inhibitor development as well. After Welch appointed me as consultant, I approached John Laragh during a lunch at Columbia University whether he would be interested in an ACE inhibitor for clinical trials (37) .

Early on, studies indicated a need for drugs that interfere with Ang II activities, because its excess could cause myocardial and renal tubular necrosis. Haralambos Gavras set out to study the effects of Ang II inhibitors on systemic blood pressure and coronary and renal circulation. Together with Brunner, Laragh, and colleagues, he found that suppression of Ang II release by inhibiting ACE was an effective treatment for hypertension and heart failure (39 40 41) . First, they administered the undecapeptide teprotide parenterally; later, they used captopril orally.

The model for synthesizing an orally active ACE inhibitor was carboxypeptidase A, but this structure-based drug design later turned out to be quite a fortunate guess. After screening a number of compounds, Cushman and Ondetti selected captopril as the best inhibitor. Captopril has an SH group that is not oxidized after absorption from GI tract. When the inhibitor couples with ACE, it binds the Zn2+ cofactor of the enzyme (42) . Crystallization of the ACE C-domain showed that while the three dimensional structure of this domain is unrelated to carboxypeptidase A; it resembles neprilysin and other enzymes (43) .

The next ACE inhibitors were the prodrugs enalapril (44) and ramipril and others followed. The clinical effects of ACE inhibitors were investigated in a large number of patients. They reduced morbidity and mortality, also quite independently of lowering elevated blood pressure (45) .

PEPTIDE METABOLITES

Throughout these advances in therapeutics, and the rapid progress in molecular genetics and genetic engineering, I remained an unreconstructed enzymologist. My attitude is best characterized by Kirchner (46) , "I sometimes wonder if I have witnessed almost the entire molecular biology revolution, only to emerge unscathed as an unrepentant and un-rehabilitated biochemist." I would say an un-rehabilitated biochemical pharmacologist. Results from many laboratories, including our own (25) , indicated intricate mechanisms for release of active enzymatic metabolites of Ang I and BK to justify our continued interest.

Inhibition of ACE increases the substrate level for some enzymes that metabolize Ang I and BK. Some metabolites are mediators with actions different than the peptides (BK or Ang I and II) they derived from have.

BK and kallidin (Lys-BK) are also cleaved at the N terminus. When an aminopeptidase removes Lys1 from Lys-BK, it converts to BK that can be cleaved further, at Arg1-Pro2 by another aminopeptidase. We first found this enzyme in erythrocytes then in the kidney (47 , 48) , and it is now called peptidase P (24) .

Neprilysin also converts Ang I to Ang 1–7 (49) and deamidase or cathepsin A to Ang 1–9 (25) . These peptides enhance the effects of BK on its B2 receptors in cultured cells (50) . Ang 1–7 is liberated from Ang II by prolylcarboxypeptidase (51) , but also by the recently described ACE 2, a carboxypeptidase (52) . (If the name ACE is not proper for an enzyme which cleaves other substrates with more favorable kinetics (53) than Ang I, ACE 2 for the structurally related carboxypeptidase is even worse.) It hydrolyzes Ang I only very slowly, compared with Ang II (50 , 52) . Ang 1–7 antagonizes many effects of Ang II, potentiates BK, and has its own receptors (54) .

When the C-terminal Arg of BK or Lys-BK is removed by plasma carboxypeptidase N or M in membranes, we discovered (24) the resulting des-Arg-kinin action on B1 receptors different from B2 receptors of intact BK (55 , 56) . Both human B1 receptors and ACE have a canonical Zn2+ binding pentamer, where ACE inhibitors attach to both proteins. Indeed, ACE inhibitors activate B1 receptors in cultured cells to release NO, even in absence of ACE expression (57 , 58) .

ACE AND ITS INHIBITORS, CONTINUING DEVELOPMENTS

The fact that ACE has two active N- and C-domains with different properties (21 22 23) expands the potential use of ACE inhibitors. Blocking the hydrolysis of the myeloprotective tetrapeptide AcSer-Asp-Lys-Pro by the N-domain of ACE protects hematopoietic stem cells during aggressive chemotherapy (22) , and alleviates collagen accumulation in rat hearts (59) .

Inclusion (II) or deletion (DD) of 287 base pairs in intron 16 can regulate human plasma ACE level (60) . The relevance in human pathology of this difference in genotype has been the subject of many clinical studies, frequently without a definite conclusion. Nevertheless, participation of plasma ACE in the therapeutic effects of ACE inhibitors is questionable.

ACE inhibitors have activities that cannot be explained entirely by blocking either Ang I or BK hydrolysis, this prompted us to study the cellular, subcellular, and molecular modes of their actions. An early paper on captopril already suggested (in hindsight) the separation of ACE inhibition from BK potentiation. Stepwise increased captopril concentrations continued to enhance sooth muscle stimulation by BK beyond the concentration needed to inhibit ACE (61) . In cells expressing both ACE and BK B2 receptors, ACE inhibitors augment BK activity independently of blocking inactivation (25) , shown also with ACE-resistant BK analogs (50 , 62) . That is interpreted as crosstalk between ACE and B2 receptors, resulting in a more favorable conformational change. ACE inhibitors that do not directly affect B2 receptors can be allosteric enhancers of the B2 receptor agonists (50) . Because of the spatially very close expression of the enzyme and receptors on cell membranes after transfection, they can form heterodimers (62 ; Chen et al., to be published).

QUESTIONS REMAINING

This is by no means the end of the history of ACE; plenty of questions await answers. For example, outsiders can still ask, what changes in knockout mice are due to the lack of a complete ACE gene and which are caused by mouse body compensating for its absence? Or why NF-{kappa}B should really be the amen in many papers?

The highest concentration of human ACE is in the microvillar structure of the proximal tubules, and also of small intestine, placenta, and choroid plexus (24 , 53) . Thus, ACE on the luminal surface of conduits facing body fluids can be involved in absorption, but of what? For example, in the intestine the ACE could release C-terminal dipeptides from protein digests and they may be absorbed faster than single amino acids.

Can well-established facts concerning ACE be reconciled with some recent and older contradictory findings? Kinetics of ACE show that it effectively hydrolyzes peptides only up to 12–13 amino acids (53) . But after longer incubation, ACE cleaved the 30 residue long B chain of insulin (17 , 53) or the 40–42 residue long amyloid ß protein, important in Alzheimer’s disease (63) . Most circulating peptides have only a transient encounter with the ACE on endothelial surfaces, but after longer contact ACE could cleave larger active peptide substrates, not necessarily at C-terminal end. ACE hydrolyzes the N-terminal tripeptide of luteinizing hormone releasing hormone (25 , 53) and the amyloid ß-protein at Asp7-Ser8(64).

EPILOGUE

The debate (35 36 37 38 39) on sharing credit for the development of ACE inhibitors can be summarized by paraphrasing a statement of President John F. Kennedy. A drug that sells for billions of dollars has many parents, while another, which cannot be marketed after clinical testing, is an orphan. This also reminds me of a Hungarian anecdote. A friend consoling a distraught husband, whose wife repeatedly made him a cuckold, explains that it is far better to have 10 percent interest in a flourishing business than 100 percent in a bankrupt one.

This story of the ACE inhibitors, given to tens of millions of patients, is far from complete. As their putative, possible, or proven applications continue to evolve (45 , 58) , it becomes difficult to predict future developments. I only partially summarized the slow beginnings of research on the RAS and KKS. I did so hoping that the names of those first investigators of such talent are not written on sand. Without the contributions of individuals such as W. T. Beraldo, E. Braun-Menendez, E. K. Frey, I. H. Page, M. Rocha e Silva, L. T. Skeggs, Jr., J. Vane, A. D. Welch, E. Werle and others, we would not have ACE inhibitors.

Shakespeare wrote in the Comedy of Errors, "We came into the world like brother and brother; And now let’s go hand in hand, not one before another" (Act V, Scene I; 26).


Figure 2
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  		Figure 2.

ACKNOWLEDGMENTS

We have been supported throughout the years by the NHLBI of NIH. I am grateful for the advice of Dr. A.R. Johnson-Zeiger and for the editorial assistance of Ms. Cynthia Sanders.

FOOTNOTES

The opinions expressed in editorials, essays, letters to the editor, and other articles comprising the Up Front section are those of the authors and do not necessarily reflect the opinions of FASEB or its constituent societies. The FASEB Journal welcomes all points of view and many voices. We look forward to hearing these in the form of op-ed pieces and/or letters from its readers addressed to journals{at}faseb.org.

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