Prolidase requires activation for its enzymatic activity. Phosphorylation of prolidase has been identified as a potential mechanism for regulating its enzymatic activity (Figure 3). Prolidase activity was reduced in fibroblasts treated with erbstatin, a naturally occurring inhibitor of tyrosine-specific protein kinase. The same study showed that an anti-phosphotyrosine antibody also reduced prolidase activity in a dose-dependent manner while phosphotyrosine phosphatase 1B increased prolidase activity (Surazyński et al., 2001). Serine/threonine phosphorylation of prolidase was also reported in fibroblasts treated with nitric oxide, which mediates inflammatory responses, wound repair, and angiogenesis (Surazynski et al., 2005). In another study, prolidase activity was shown to be decreased in fibroblasts from fasting rats. Fasting results in ATP depletion, leading to accumulation of inorganic phosphate and pyruvate kinase activity inhibition, affecting phosphoenolpyruvate (PEP) conversion into pyruvate. The authors postulated that the accumulating PEP may form a complex with prolidase and prevent its phosphorylation or stimulate its dephosphorylation; however, the exact mechanism remains unknown (Cechowska-Pasko et al., 2004). The same research group demonstrated that thrombin, the enzyme that converts fibrinogen to fibrin in the blood clotting cascade, inhibits prolidase expression while inducing its phosphorylation in colorectal adenocarcinoma cells (Lundblad et al., 2004; Karna et al., 2012). However, thrombin binds to the β1 integrin receptor and increases prolidase activity in human dermal fibroblasts (Surazyński et al., 2005).
Another common symptom is breathing problems stemming from a cystic fibrosis (CF)-like phenotype (Luder et al., 2007; Cottin et al., 2020). Immunoglobulin levels are higher in PD patients due to the binding of gamma globulins to prolidase substrates in blood serum, and PD patients suffer from recurrent infections due to open sores on the skin and infections in the respiratory tract (Jackson and Heininger, 1975; Sheffield et al., 1977; Cleary et al., 1994). Other than collagen, these imidodipeptide substrates are common in immunoglobulins and Clq in complement (Reid, 2018). Another immune related symptom includes a systemic lupus erythematosus (SLE)-like phenotype (Butbul Aviel et al., 2012; Kurien et al., 2013; Chidambaram et al., 2021). The mechanism by which SLE is associated with PD is not clear although, as in the case of CF, a role for a high proline containing defective C1q complement has been proposed (Chidambaram et al., 2021).
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