Carboxypeptidase N: a pleiotropic regulator of inflammation

Matthews, Kirstin R.W.; Mueller‐Ortiz, Stacey L.; Wetsel, Rick A.

doi:10.1016/j.molimm.2003.10.002

Cited by 148 publications

(118 citation statements)

References 66 publications

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“…CPN is synthesized by the liver and secreted into the blood where its concentration is high, approximately 30 μg/ml ( 10 −7 M) [8,31]. As determined by Northern analysis (Tan and Skidgel, unpublished)[32], the liver is its only site of synthesis, however, only low levels of CPN can be extracted from the organ itself [9].…”

Section: Localizationmentioning

confidence: 99%

“…However, most of the active site residues are conserved among the metallocarboxypeptidases and all require zinc as cofactor for activity [17,21,31]. …”

Section: Comparison To Related Carboxypeptidasesmentioning

confidence: 99%

“…CPN cleaves only C-terminal Arg or Lys from peptides or proteins [21,31,39]. In general, the enzyme cleaves off C-terminal Lys faster than Arg due to a higher turnover number.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

“…Because peptide hormones like kinins are primarily autocrine or paracrine hormones and their sites of action are restricted to a small local area, the levels of circulating peptides are likely to represent "spillover" of peptides generated at local sites. High concentrations of kinins in the blood can have noxious effects, thus blood enzymes like CPN can be protective and prevent the buildup of potentially harmful levels in the circulation [17,21,31]. CPN exists at a relatively high level in blood (~30 μg/ml) and is also of obvious relevance in the inactivation of anaphylatoxins [23,31].…”

mentioning

confidence: 99%

“…High concentrations of kinins in the blood can have noxious effects, thus blood enzymes like CPN can be protective and prevent the buildup of potentially harmful levels in the circulation [17,21,31]. CPN exists at a relatively high level in blood (~30 μg/ml) and is also of obvious relevance in the inactivation of anaphylatoxins [23,31]. In fact, no one has been found who completely lacks the enzyme and even patients with low enzyme levels are rarely encountered [29,30].…”

mentioning

confidence: 99%

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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: Localizationmentioning

confidence: 99%

“…However, most of the active site residues are conserved among the metallocarboxypeptidases and all require zinc as cofactor for activity [17,21,31]. …”

Section: Comparison To Related Carboxypeptidasesmentioning

confidence: 99%

“…CPN cleaves only C-terminal Arg or Lys from peptides or proteins [21,31,39]. In general, the enzyme cleaves off C-terminal Lys faster than Arg due to a higher turnover number.…”

Section: Nih-pa Author Manuscriptmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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

Skidgel

Erdös

2007

International Immunopharmacology

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C ‐terminal Lys or Arg Clipping in Proteins

2019

Co and Post‐Translational Modifications of Therapeutic Antibodies and Proteins

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Review: The Evolving Landscape for Complement Therapeutics in Rheumatic and Autoimmune Diseases

Thurman

Frazer‐Abel

Holers

2017

Arthritis & Rheumatology

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The complement system is increasingly understood to play major roles in the pathogenesis of human inflammatory and autoimmune diseases. Because of this situation, there are rapidly expanding commercial efforts to develop novel complement inhibitors and effector pathway–modulating drugs. This review provides insights into the evolving understanding of the complement system components, mechanisms of activation within and across the 3 pathways (classical, alternative, and lectin), how the pathways are normally controlled and then dysregulated in target tissues, and what diseases are known to be, in large part, complement‐dependent through the successful development and approval of complement therapeutics in patients. Mechanisms of complement activation in rheumatoid arthritis, lupus, and thrombotic microangiopathies are also illustrated. In addition, the specific therapeutic drugs that are both approved and under development are discussed in the context of both nonrheumatic and rheumatic diseases. Finally, the methods by which the complement system can be assessed in humans through biomarker studies are outlined, with the goal of understanding, in specific patients, how the system is functioning.

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Carboxypeptidase N: a pleiotropic regulator of inflammation

Cited by 148 publications

References 66 publications

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

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

C ‐terminal Lys or Arg Clipping in Proteins

Review: The Evolving Landscape for Complement Therapeutics in Rheumatic and Autoimmune Diseases

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