General · EdgepediaSeptember 17, 20267 min read

Cathepsin C

Dipeptidyl-peptidase I (DPP I; EC 3.4.14.1), also known as cathepsin C, is a lysosomal cysteine protease of the papain-like family that removes N-terminal dipeptides from polypeptide substrates. Its best-understood physiological role is the activation of serine protease zymogens in immune cells: it converts inactive proenzymes of neutrophils, mast cells, and cytotoxic lymphocytes into their active forms by cleaving a two-residue N-terminal propeptide.¹^•² Because this step drives neutrophil-mediated tissue damage in inflammatory lung disease, the enzyme has become a drug target, and the inhibitor brensocatib was approved by the United States Food and Drug Administration in August 2025 for non-cystic fibrosis bronchiectasis.³

Key fact	Detail
Enzyme classification	EC 3.4.14.1, dipeptidyl-peptidase I; name recommended by the IUBMB Nomenclature Committee in 1981⁴
Reaction type	Stepwise hydrolysis of N-terminal dipeptides from polypeptides; an exopeptidase, not an endopeptidase²
Principal substrates	Neutrophil elastase, proteinase 3, cathepsin G, and neutrophil serine protease 4, plus mast cell chymase and tryptase and lymphocyte granzymes A and B⁵
Oligomeric structure	Mature human enzyme is a homotetramer, a dimer of dimers, held together by its exclusion domain²
Cofactor requirement	Activated by chloride ions at pH below 7, a feature that distinguishes it from other papain-like peptidases²
Deficiency phenotype	Loss-of-function variants in the cathepsin C gene cause Papillon-Lefèvre syndrome and Haim-Munk syndrome, marked by severe periodontal disease and skin thickening⁵
Approved drug	Brensocatib (BRINSUPRI), an oral reversible DPP-1 inhibitor, FDA-approved August 12, 2025 for non-cystic fibrosis bronchiectasis in patients 12 years and older³

Name and history

The enzyme was discovered in 1948 in pig kidney by Gutman and Fruton and described as having chymotrypsin-like specificity; Tallan and co-workers termed it cathepsin C in 1952.⁶ It was also known as glucagon-degrading enzyme and dipeptidyl transferase. McDonald later renamed it dipeptidyl arylamidase I and then dipeptidyl aminopeptidase I, in recognition of its exopeptidase activity; in semisystematic nomenclature, dipeptidyl peptidase describes the hydrolysis of an N-terminal dipeptide from a polypeptide. The IUBMB Nomenclature Committee recommended the name dipeptidyl-peptidase I with the number EC 3.4.14.1 in 1981.⁴ A high molecular mass, thiol-dependent enzyme once termed cathepsin J was later shown to be identical to DPP I.⁴

Structure and enzymatic mechanism

Cathepsin C belongs to the papain-like family of cysteine peptidases (family C1, clan CA in the MEROPS database) and is synthesized as an inactive precursor, procathepsin C, of about 60 kDa per subunit.² Its active site contains a Cys234-His381 catalytic dyad. What sets it apart from other family members is an additional exclusion domain, whose fold resembles that of metalloprotease inhibitors. After removal of the propeptide, the exclusion domain remains non-covalently bound to the peptidase domain and sterically blocks access to the active site beyond the S2 binding site, which is what makes the enzyme a dipeptidyl-peptidase rather than a broader endopeptidase.²

Several structural features govern specificity. The side chain of residue Asp1 anchors the N-terminal amino group of the substrate, and the S2 pocket is a deep hydrophobic site containing a chloride ion; the chloride is required for enzyme activity below pH 7.⁵^•² The enzyme has relatively broad substrate specificity and cleaves two-residue units stepwise until it reaches a stop sequence: it halts when the N-terminal amino group is blocked, when a proline residue is adjacent to the cleavage site, or when the N-terminal residues are lysine or arginine.² Unlike most cysteine cathepsins, which are monomers, mature human cathepsin C is a homotetramer organized as a dimer of dimers, and the exclusion domain is indispensable for tetramer formation; the tetrameric form appears restricted to animal homologs.²

Procathepsin C cannot activate itself. It is transported to lysosomes via the mannose-6-phosphate pathway and must be processed by other lysosomal peptidases; cathepsins L and S were identified as the first activating enzymes, and cathepsins F, K, and V have since been shown to activate it in vitro, indicating a redundant maturation process.²

Role in immune cell protease activation

The enzyme's central physiological role is the constitutive activation of a subgroup of serine protease zymogens in neutrophils, monocytes, mast cells, and lymphocytes. During neutrophil maturation in the bone marrow, DPP-1 removes the N-terminal dipeptide from neutrophil elastase, proteinase 3, cathepsin G, and neutrophil serine protease 4, allowing the active enzymes to be packaged into granules before the neutrophil enters the circulation.⁷^•⁵ It likewise processes granzymes A and B in cytotoxic T lymphocytes and chymase in mast cells; the zymogens carry a two-residue N-terminal propeptide whose removal by cathepsin C produces a catalytically competent active site.²

When activated neutrophils release these stored proteases, they can degrade extracellular matrix components, producing tissue damage and chronic inflammation.² In bronchiectasis, elevated levels of neutrophil elastase, proteinase 3, and cathepsin G are thought to overwhelm natural inhibitors such as alpha-1 antitrypsin and secretory leukocyte protease inhibitor, altering the airway microenvironment and increasing infection risk.⁷

Cathepsin C deficiency in humans

Loss-of-function variants in the cathepsin C gene (CTSC) cause rare autosomal recessive disorders: Papillon-Lefèvre syndrome, which presents in children around 1 to 5 years of age, and Haim-Munk syndrome, both characterized by severe periodontal disease and palmoplantar keratoderma, along with increased susceptibility to infection.⁵^•⁸ These phenotypes are informative for drug development: because brensocatib targets DPP-1, the skin and periodontal features of the deficiency syndrome were pre-defined as adverse events of special interest in its clinical trials.⁸

Pharmacological inhibition and brensocatib

DPP-1 inhibition is intended to reduce the activity of downstream neutrophil serine proteases without directly blocking each protease. An early irreversible inhibitor, GSK-2793660, reduced neutrophil serine protease activity in a phase I trial but was limited in clinical application by epidermal desquamation.⁵

Brensocatib (formerly AZD7986; INS1007) is an oral, selective, competitive, and reversible inhibitor of DPP-1.⁷ In the phase 2 WILLOW trial, 256 patients with bronchiectasis who had had at least two exacerbations in the previous year were randomized to placebo, 10 mg, or 25 mg of brensocatib once daily for 24 weeks. The adjusted hazard ratio for exacerbation versus placebo was 0.58 (95% CI, 0.35 to 0.95) in the 10-mg group and 0.62 (95% CI, 0.38 to 0.99) in the 25-mg group, and sputum neutrophil elastase activity fell from baseline with both doses.⁷ The incidence of dental adverse events was higher with the 10-mg dose and of skin adverse events with the 25-mg dose than with placebo.⁷

The phase 3 ASPEN trial evaluated 10 mg and 25 mg once daily over 52 weeks. The annualized rate of pulmonary exacerbations was 1.02 with 10 mg and 1.04 with 25 mg versus 1.29 with placebo (rate ratios 0.79 and 0.81), and the 25-mg dose slowed lung function decline: post-bronchodilator FEV1 fell 24 mL versus 62 mL with placebo, a difference of 38 mL (95% CI, 11 to 65).³ On the basis of these trials, the FDA approved brensocatib as BRINSUPRI on August 12, 2025 for non-cystic fibrosis bronchiectasis in adults and pediatric patients 12 years of age and older; the agency noted that no previously approved drug shared this mechanism of action.³^•⁸ Common side effects in ASPEN included upper respiratory tract infections, headache, rash, dry skin, hyperkeratosis, and hypertension, with some occurring more often at the 25-mg dose.³

DPP-1 inhibition is also being evaluated beyond bronchiectasis. Dysregulation of CTSC has been linked to chronic obstructive pulmonary disease, asthma, cystic fibrosis, and COVID-19-related acute respiratory distress syndrome, and a phase IIa trial assessed brensocatib pharmacokinetics, safety, and tolerability in adults with cystic fibrosis, finding profiles comparable to those in healthy adults and patients with bronchiectasis.⁵^•⁹ In the STOP-COVID19 trial of brensocatib 25 mg in patients hospitalized for severe COVID-19 in the United Kingdom, the drug did not improve clinical outcomes at day 29 in the primary analysis.¹⁰

References

Topic: Encyclopedia › Life and health › Biological foundations › Biochemistry and metabolism › Enzyme classes and activities › Proteolytic and peptidase enzymes › Proteases by catalytic mechanism › Cysteine proteases › Papain family (C1) › Non-cathepsin animal papain-fold proteases

Initially written Sep 17, 2026 · Reviewed: Sep 30, 2026; Oct 21, 2026 · Edited: Sep 30, 2026; Oct 11, 2026; Oct 21, 2026 · Last review: Oct 21, 2026

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