Über Proteinase und Carboxy‐Polypeptidase aus Pankreas (XVII. Mitteilung zur Spezifität tierischer Proteasen)

Waldschmidt-Leitz, Ernst; Purr, Arnulf

doi:10.1002/cber.19290620857

Cited by 43 publications

(14 citation statements)

References 10 publications

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“…Carboxypeptidases were initially isolated from pancreatic extracts and so were associated with protein and peptide degradation in the digestive tract [1][2][3][4]. However, work beginning in the early 1960's by Erdös and Sloane [5] revealed the presence of a novel carboxypeptidase in the blood that plays a regulatory role by inactivating bradykinin via removal of its C-terminal Arg residue.…”

Section: Historymentioning

confidence: 99%

Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Skidgel

Erdös

2007

International Immunopharmacology

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Human carboxypeptidase N (CPN) was discovered in the early 1960s as a plasma enzyme that inactivates bradykinin and was identified 8 years later as the major "anaphylatoxin inactivator" of blood. CPN plays in important role in protecting the body from excessive buildup of potentially deleterious peptides that normally act as local autocrine or paracrine hormones. This review summarizes the structure, enzymatic properties and function of this important human enzyme, including insights gained by the recent elucidation of the crystal structure of the CPN catalytic subunit and structural modeling of the non-catalytic regulatory 83 kDa subunit. We also discuss its physiological role in cleaving substrates such as kinins, anaphylatoxins, creatine kinase, plasminogen receptors, hemoglobin and stromal cell-derived factor-1α (SDF-1α). HistoryCarboxypeptidases were initially isolated from pancreatic extracts and so were associated with protein and peptide degradation in the digestive tract [1][2][3][4]. However, work beginning in the early 1960's by Erdös and Sloane [5] revealed the presence of a novel carboxypeptidase in the blood that plays a regulatory role by inactivating bradykinin via removal of its C-terminal Arg residue. (Subsequent research some 2 decades later led to the discovery of a second kinin B 1 receptor activated by the carboxypeptidase metabolite that is its endogenous agonist -see below). Initially it was assumed that the enzyme represents a circulating form of pancreatic carboxypeptidase B, but this was disproved by the characterization of its enzymatic properties [5][6][7][8], which was later borne out by biochemical studies, sequence analysis [9][10][11][12][13][14][15] and ultimately X-ray crystallography [16]. To differentiate it from the pancreatic enzyme, it was named carboxypeptidase N (CPN; EC 3.4.17.3) and was the first member of a family of carboxypeptidases now known as the regulatory or CPN/E subfamily of metallocarboxypeptidases [17][18][19]. It has since been re-discovered many times as other substrates were found and so has acquired aliases such as creatine kinase conversion factor, plasma carboxypeptidase B, arginine carboxypeptidase, lysine carboxypeptidase and protaminase [8,17,20,21]. The most notable was the finding by Bokisch and Müller-Eberhard in 1969 -70 [22,23] that the human plasma "anaphylatoxin inactivator" is identical with CPN. This finding explains our interest in the work of Dr. Tony Hugli, who has made many seminal contributions to the understanding of the structure and function of anaphylatoxins [24][25][26][27]. In Send Correspondence and Proofs To: Randal A. Skidgel, PhD, Dept. of Pharmacology (M/C 868), Univ. of Illinois College of Medicine, 835 S. Wolcott, Chicago, IL 60612, Phone: 312-996-9179, FAX: 312-996-1648, EMAIL: E-mail: rskidgel@uic.edu. Publisher's Disclaimer: This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript w...

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Section: Historymentioning

confidence: 99%

Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Skidgel

Erdös

2007

International Immunopharmacology

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“…pK Assignments. CPA is known to be reasonably active only in the pH range of approximately 6-9, with an optimum around pH 7.5 (34). Several kinetic studies (35)(36)(37)(38)(39)(40)(41)(42)(43) relate to the details of pH-activity relationships in the hydrolysis catalyzed by CPA and contain attempts to assign the usually observed high (z9) and low (-6-6.5) pKs to specific catalytic groups (44,45).…”

Section: Discussionmentioning

confidence: 99%

Effects of pH on the structure and function of carboxypeptidase A: crystallographic studies.

Shoham¹,

Rees²,

Lipscomb³

1984

Proc. Natl. Acad. Sci. U.S.A.

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High-resolution crystal structures are described for carboxypeptidase A (EC 3.4.17.1) in crystals grown at pH 8.5, 9.0, and 9.5 and compared with the structure at pH 7.5. The comparison shows that in the pH range of 7.5-9.5 the enzyme structure is practically unchanged, and, most importantly, that the flexible side chain of Tyt-248 remains exclusively in the "up" position, awdy from the Zn atom, throughout the pH range. There is no evidence fdr binding of Tyr-248 to Zn at any of these pH values. We conclude that the interaction of Tyr-248 with Zn is not an essential part of the mechanism of carboxypeptidase A and that its occurrence is an artifact of chemical modification of Tyr-248. It is also suggested that Tyr-248 is not uniquely associated with the observed high pK of the enzymatic hydrolysis.Carboxypeptidase A (CPA; peptidyl-L-amino acid hydrolase, EC 3.4.17.1) catalyzes the hydrolysis of the carboxylterminal residue from peptide or ester substrates by cleavage of the peptide or ester bond. The three-dimensional structure is known to a resolution of 1.54 A (1). Various mechanisms for the activity of CPA toward substrates have been proposed (2) and recently reviewed (3-7). Of the potential catalytic groups that are in the region of substrate in the x-ray diffraction studies [Glu-270, L3-Zn-OH2 (in which L is a protein ligand), H20, and Tyr-248], we examine here the possible roles of Tyr-248.Studies of spectral changes of [248-arsanilazotyrosine]-CPA (arsanilazo-CPA) as a function of pH (8, 9) have indicated that the phenolic oxygen of the modified Tyr-248 is bound to the Zn in the unliganded enzyme. On the bdsis of the results of these studies (8, 9) and related ones (10-18) it has been suggested that the phenolic group of Tyr-248 is directly bound to the Zn atom ("Zn-bound Tyr-248" cohformation) in the native unliganded enzyme, and that movement of Tyr-248 away from the Zn is an essential step in catalysis of the unmodified enzyme as substrates bind (8-18). In contrast, the crystallographic studies indicate that in the unmodified enzyme the side chain oxygen of Tyr-248 is about 17 A away from the Zn (1, 2) (the "up" position) and that the phenolic oxygen moves about 12 A toward the active site as substrates bind (2, 19) (the "down" position). Moreover, a study at 1.5-A resolution shows that at pH 7.5 there is no observable binding of Tyr-248 to the Zn in the unmodified enzyme (1). In a study of the three-dimensional structure of the complex of CPA with the 39-amino acid inhibitor from the potato (PCI), it was shown that cleavage has taken place and thatTyr-248 donates a hydrogen bond to the newly foftned carboxylate anion and receives a hydrogen bond from the originally penultimate peptide bond (20). Whether Tyr-248 has other roles such as a proton donor in the cleavage reaction (2-5) or whether formation of a bond between Tyr-248 and Zn is an essential step (8, 9) in the activity of CPA are open to question. In this paper we report a crystallographic study that extends the earlier study of the nati...

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“…One important area of carboxypeptidase function is in the digestion of dietary proteins and peptides to release amino acids that are able to be absorbed in the intestinal tract (5). This activity was identified more than 80 years ago when the first CP, originally called simply "carboxypeptidase," was found to be produced in large quantities by the pancreas and secreted into the intestine for dietary protein digestion (6). A second pancreatic carboxypeptidase was subsequently identified and named CPB for its substrate specificity toward basic C-terminal amino acids (7), and the first carboxypeptidase was renamed CPA for its aliphatic/aromatic amino acid specificity.…”

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confidence: 99%

Carboxypeptidase O Is a Glycosylphosphatidylinositol-anchored Intestinal Peptidase with Acidic Amino Acid Specificity

Lyons

Fricker

2011

Journal of Biological Chemistry

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Background: All previously characterized metallocarboxypeptidases of the A/B subfamily are secreted enzymes that cleave aliphatic or basic residues and are initially produced as inactive proenzymes. Results: Carboxypeptidase O is a membrane-anchored intestinal enzyme that cleaves acidic residues and is not made from a proenzyme. Conclusion: Carboxypeptidase O is distinct from other metallocarboxypeptidases. Significance: Carboxypeptidase O plays a unique physiological role in the intestinal release of acidic amino acids from dietary peptides and proteins.

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Über Proteinase und Carboxy‐Polypeptidase aus Pankreas (XVII. Mitteilung zur Spezifität tierischer Proteasen)

Cited by 43 publications

References 10 publications

Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Structure and function of human plasma carboxypeptidase N, the anaphylatoxin inactivator

Effects of pH on the structure and function of carboxypeptidase A: crystallographic studies.

Carboxypeptidase O Is a Glycosylphosphatidylinositol-anchored Intestinal Peptidase with Acidic Amino Acid Specificity

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