Antioxidant and tissue repair protein with reductase, heme-binding and radical-scavenging activities. Removes and protects against harmful oxidants and repairs macromolecules in intravascular and extravascular spaces and in intracellular compartments (   , ). Intravascularly, plays a regulatory role in red cell homeostasis by preventing heme- and reactive oxygen species-induced cell damage. Binds and degrades free heme to protect fetal and adult red blood cells from hemolysis (, ). Reduces extracellular methemoglobin, a Fe3+ (ferric) form of hemoglobin that cannot bind oxygen, back to the Fe2+ (ferrous) form deoxyhemoglobin, which has oxygen-carrying potential . Upon acute inflammation, inhibits oxidation of low-density lipoprotein particles by MPO and limits vascular damage . Extravascularly, protects from oxidation products formed on extracellular matrix structures and cell membranes. Catalyzes the reduction of carbonyl groups on oxidized collagen fibers and preserves cellular and extracellular matrix ultrastructures (, ). Importantly, counteracts the oxidative damage at blood-placenta interface, preventing leakage of free fetal hemoglobin into the maternal circulation . Intracellularly, has a role in maintaining mitochondrial redox homeostasis. Bound to complex I of the respiratory chain of mitochondria, may scavenge free radicals and preserve mitochondrial ATP synthesis. Protects renal tubule epithelial cells from heme-induced oxidative damage to mitochondria (, ). Reduces cytochrome c from Fe3+ (ferric) to the Fe2+ (ferrous) state through formation of superoxide anion radicals in the presence of ascorbate or NADH/NADPH electron donor cofactors, ascorbate being the preferred cofactor . Has a chaperone role in facilitating the correct folding of bikunin in the endoplasmic reticulum compartment (By similarity).
Kunitz-type serine protease inhibitor and structural component of extracellular matrix with a role in extracellular space remodeling and cell adhesion (, ). Among others, has antiprotease activity toward kallikrein, a protease involved in airway inflammation; inhibits GZMK/granzyme, a granule-stored serine protease involved in NK and T cell cytotoxic responses; and inhibits PLG/plasmin, a protease required for activation of matrix metalloproteinases ( ). As part of I-alpha-I complex, provides for the heavy chains to be transferred from I-alpha-I complex to hyaluronan in the presence of TNFAIP6, in a dynamic process that releases free bikunin and remodels extracellular matrix proteoglycan structures. Free bikunin, but not its heavy chain-bound form, acts as potent protease inhibitor in airway secretions . Part of hyaluronan-rich extracellular matrix that surrounds oocyte during cumulus oophorus expansion, an indispensable process for proper ovulation (By similarity). Also inhibits calcium oxalate crystallization .
Kunitz-type serine protease inhibitor. Has high catalytic efficiency for F10/blood coagulation factor Xa and may act as an anticoagulant by inhibiting prothrombin activation. Inhibits trypsin and mast cell CMA1/chymase and tryptase proteases.
Subcellular locations: Secreted, Endoplasmic reticulum, Cytoplasm, Cytosol, Cell membrane, Nucleus membrane, Mitochondrion inner membrane, Secreted, Extracellular space, Extracellular matrix
The cellular uptake occurs via a non-endocytotic pathway and allows for localization to various membrane structures. A specific binding to plasma membrane suggests the presence of a cell receptor, yet to be identified. Directly binds collagen fibers type I.
Subcellular locations: Secreted
Expressed by the liver and secreted in plasma. Occurs in many physiological fluids including plasma, urine, and cerebrospinal fluid . Expressed in epidermal keratinocytes, in dermis and epidermal-dermal junction (at protein level) . Expressed in red blood cells (at protein level) . Expressed in placenta .
Detected in placenta (at protein level) . Detected in cerebrospinal fluid, plasma and urine (at protein level) ( ). Expressed in airway epithelium and submucosal gland (at protein level). Colocalizes with TNFAIP6 at the ciliary border. Present in bronchoalveolar lavage fluid (at protein level).