Human prolidase and prolidase deficiency: an overview on the characterization of the enzyme involved in proline recycling and on the effects of its mutations

Abstract

Here we summarized what is known at the present about function, structure and effect of mutations in the human prolidase. Among the peptidases, prolidase is the only metalloenzyme that cleaves the iminodipeptides containing a proline or hydroxyproline residue at the C-terminal end. It is relevant in the latest stage of protein catabolism, particularly of those molecules rich in imino acids such as collagens, thus being involved in matrix remodelling. Beside its intracellular functions, prolidase has an antitoxic effect against some organophosphorus molecules, can be used in dietary industry as bitterness reducing agent and recently has been used as target enzyme for specific melanoma prodrug activation. Recombinant human prolidase was produced in prokaryotic and eukaryotic hosts with biochemical properties similar to the endogenous enzyme and represents a valid tool both to better understand the structure and biological function of the enzyme and to develop an enzyme replacement therapy for the prolidase deficiency (PD). Prolidase deficiency is a rare recessive disorder caused by mutations in the prolidase gene and characterized by severe skin lesions. Single amino acid substitutions, exon splicing, deletions and a duplication were described as causative for the disease and are mainly located at highly conserved amino acids in the sequence of prolidase from different species. The pathophysiology of PD is still poorly understood; we offer here a review of the molecular mechanisms so far hypothesized.

Prolidase deficiency associated with systemic lupus erythematosus (SLE): single site experience and literature review

“…Prolidase has a major role in the recycling of proline released during the degradation of collagen and dietary proteins [11]. Although there is considerable knowledge concerning the putative roles of the prolidase enzyme [12], the pathophysiology of PD remains an enigma.…”

Prolidase Deficiency in a Mexican-American Patient Identified by Array CGH Reveals a Novel and the Largest PEPD Gene Deletion

“…For this reason, the carbohydrate-deficient transferrin studies were tested and found negative, ruling out congenital disorders of glycosylation. Notably, SLE has been linked to PD [Bissonnette et al, 1993;Shrinath et al, 1997;Di Rocco et al, 2007] and is associated with multiple mutations [Lupi et al, 2006[Lupi et al, , 2008Falik-Zaccai et al, 2010;Klar et al, 2010;Butbul Aviel et al, 2012]. The mechanistic relationship between these entities is not clear, but a loss of immune tolerance to lupus-associated autoantigens in PD has been hypothesized, leading to positive antinuclear antibodies and other autoantibody testing even in patients without clinical SLE [Kurien et al, 2013].…”

“…To date, ∼ 90 patients with PD have been described, 67 of which have been molecularly characterized revealing 28 distinct mutant alleles [Tanoue et al, 1990[Tanoue et al, , 1991Ledoux et al, 1994Ledoux et al, , 1996Kikuchi et al, 2000;Forlino et al, 2002;Lupi et al, 2004Lupi et al, , 2006Lupi et al, , 2008Hershkovitz et al, 2006;Wang et al, 2006;Falik-Zaccai et al, 2010;Klar et al, 2010;Butbul Aviel et al, 2012;Caselli et al, 2012;Pandit et al, 2013;Besio et al, 2015]. The PEPD gene is over 130 kb long and is comprised of 15 exons.…”

A broad spectrum of developmental delay in a large cohort of prolidase deficiency patients demonstrates marked interfamilial and intrafamilial phenotypic variability

“…This enzyme has a major role in the recycling of proline released during the degradation of collagen and dietary proteins [Lupi et al, 2004]. Although there is considerable knowledge concerning the putative roles of the prolidase enzyme [Lupi et al, 2008], the pathophysiology of PD remains an enigma.…”