En Route to New Therapeutic Options for Iron Overload Diseases: Matriptase‐2 as a Target for Kunitz‐Type Inhibitors

Beckmann, Anna-Madeleine; Maurer, Eva; Lülsdorff, Verena; Wilms, Annika; Furtmann, Norbert; Bajorath, Jürgen; Gütschow, Michael; Stirnberg, Marit

doi:10.1002/cbic.201500651

Cited by 21 publications

(17 citation statements)

References 36 publications

(53 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Aprotinin is a soluble membrane-impermeable serine protease inhibitor consisting of 58 amino acids. Both inhibit the proteolytic activity of MT2 (47,49,50). We reasoned that if the substrate cleavage is inhibited by both inhibitors, it would indicate that the cleavage takes place after MT2 reaches the plasma membrane.…”

Section: Mechanistic Studies Of Matriptase-2 Activitymentioning

confidence: 99%

The catalytic, stem, and transmembrane portions of matriptase-2 are required for suppressing the expression of the iron-regulatory hormone hepcidin

Mao

Wortham

Enns

et al. 2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

Edited by F. Peter Guengerich Matriptase-2 (MT2) is a type-II transmembrane, trypsin-like serine protease that is predominantly expressed in the liver. It is a key suppressor for the expression of hepatic hepcidin, an ironregulatory hormone that is induced via the bone morphogenetic protein signaling pathway. A current model predicts that MT2 suppresses hepcidin expression by cleaving multiple components of the induction pathway. MT2 is synthesized as a zymogen that undergoes autocleavage for activation and shedding. However, the biologically active form of MT2 and, importantly, the contributions of different MT2 domains to its function are largely unknown. Here we examined the activities of truncated MT2 that were generated by site-directed mutagenesis or Gibson assembly master mix, and found that the stem region of MT2 determines the specificity and efficacy for substrate cleavage. The transmembrane domain allowed MT2 activation after reaching the plasma membrane, and the cytoplasmic domain facilitated these processes. Further in vivo rescue studies indicated that the entire extracellular and transmembrane domains of MT2 are required to correct the low-hemoglobin, low-serum iron, and high-hepcidin status in MT2 ؊/؊ mice. Unlike in cell lines, no autocleavage of MT2 was detected in vivo in the liver, implying that MT2 may also function independently of its proteolytic activity. In conjunction with our previous studies implicating the cytoplasmic domain as an intracellular iron sensor, these observations reveal the importance of each MT2 domain for MT2-mediated substrate cleavage and for its biological function.

show abstract

Section: Mechanistic Studies Of Matriptase-2 Activitymentioning

confidence: 99%

The catalytic, stem, and transmembrane portions of matriptase-2 are required for suppressing the expression of the iron-regulatory hormone hepcidin

Mao

Wortham

Enns

et al. 2019

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Serum-stabilized antisense DNA (IONIS-TMPRSS6-LRx, Ionis Pharmaceuticals183,184) or liposomal siRNA (ALN-TMP, Alnylam Pharmaceuticals Inc185), block MT-2 mRNA translation, and have shown preclinical efficacy in animal models of β-thalassemia and iron overload. In addition, several physiological protease inhibitors have demonstrated specific MT-2-inhibiting activity 186, and some of them have a Kunitz domain that could be an important lead for further development of hepcidin-inducing peptides187.…”

Section: Iron Metabolism As a Therapeutic Targetmentioning

confidence: 99%

Targeting iron metabolism in drug discovery and delivery

Crielaard

Lammers

Rivella

2017

Nat Rev Drug Discov

281

205

View full text Add to dashboard Cite

Iron fulfils a central role in many essential biochemical processes in human physiology, which makes proper processing of iron crucial. Although iron metabolism is subject to relatively strict physiological control, in recent years numerous disorders, such as cancer and neurodegenerative diseases, have been linked to deregulated iron homeostasis. Because of its involvement in the pathogenesis of these diseases, iron metabolism constitutes a promising and largely unexploited therapeutic target for the development of new pharmacological treatments. Several iron metabolism-targeted therapies are already under clinical evaluation for haematological disorders, and these and newly developed therapeutic agents will likely have substantial benefit in the clinical management of iron metabolism-associated diseases, for which few efficacious treatments are often available.

show abstract

“…Recently, a Kuntiz-type hepatocyte growth factor activator inhibitor two (HAI-2) that targets and inhibits the proteolytic activity of TMPRSS6 was discovered [148]. HAI-2 prevented HJV cleavage by forming a series of hydrogen bonds and a disulphide bond within the TMPRSS6 active site which prevents hepcidin downregulation [148].…”

Section: Small Molecule Hepcidin Agonistsmentioning

confidence: 99%

Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis

et al. 2019

View full text Add to dashboard Cite

The interaction between hepcidin and ferroportin is the key mechanism involved in regulation of systemic iron homeostasis. This axis can be affected by multiple stimuli including plasma iron levels, inflammation and erythropoietic demand. Genetic defects or prolonged inflammatory stimuli results in dysregulation of this axis, which can lead to several disorders including hereditary hemochromatosis and anaemia of chronic disease. An imbalance in iron homeostasis is increasingly being associated with worse disease outcomes in many clinical conditions including multiple cancers and neurological disorders. Currently, there are limited treatment options for regulating iron levels in patients and thus significant efforts are being made to uncover approaches to regulate hepcidin and ferroportin expression. These approaches either target these molecules directly or regulatory steps which mediate hepcidin or ferroportin expression. This review examines the current status of hepcidin and ferroportin agonists and antagonists, as well as inducers and inhibitors of these proteins and their regulatory pathways.

show abstract

En Route to New Therapeutic Options for Iron Overload Diseases: Matriptase‐2 as a Target for Kunitz‐Type Inhibitors

Cited by 21 publications

References 36 publications

The catalytic, stem, and transmembrane portions of matriptase-2 are required for suppressing the expression of the iron-regulatory hormone hepcidin

The catalytic, stem, and transmembrane portions of matriptase-2 are required for suppressing the expression of the iron-regulatory hormone hepcidin

Targeting iron metabolism in drug discovery and delivery

Therapeutic Advances in Regulating the Hepcidin/Ferroportin Axis

Contact Info

Product

Resources

About