State of the Art in the Development of Human Serum Carnosinase Inhibitors

Abstract

Human serum carnosinase is an enzyme that operates the preferential hydrolysis of dipeptides with a C-terminus histidine. Only higher primates excrete such an enzyme in serum and cerebrospinal fluid. In humans, the serum hydrolytic rate has high interindividual variability owing to gene polymorphism, although age, gender, diet, and also diseases and surgical interventions can modify serum activity. Human genetic diseases with altered carnosinase activity have been identified and associated with neurological disorders and age-related cognitive decline. On the contrary, low peripheral carnosinase activity has been associated with kidney protection, especially in diabetic nephropathy. Therefore, serum carnosinase is a druggable target for the development of selective inhibitors. However, only one molecule (i.e., carnostatine) has been discovered with the purpose of developing serum carnosinase inhibitors. Bestatin is the only inhibitor reported other than carnostatine, although its activity is not selective towards serum carnosinase. Herein, we present a review of the most critical findings on human serum carnosinase, including enzyme expression, localization and substrate selectivity, along with factors affecting the hydrolytic activity, its implication in human diseases and the properties of known inhibitors of the enzyme.

Keywords: bestatin; carnosine; carnostatine; inhibitors; serum carnosinase.

Figure 1

Hydrolysis reaction catalyzed by human serum carnosinase (EC 3.4.13.20).

Figure 2

Crystal structure of human carnosine dipeptidase 1 (PDB id: 3dlj) overlapped with the crystal structure of human carnosine dipeptidase 2 (PDB id: 4ruh). (A) reports the two monomers with separate colors; (B) reports carnosine dipeptidase 1 in red and carnosine dipeptidase 2 in blue.

Figure 3

LIGPLOT diagram of main zinc interactions with human carnosine dipeptidase 1 (A,B) as from enzyme crystal structure (PDB id: 3dlj) and LIGPLOT diagram of main manganese interactions with human carnosine dipeptidase 2 (C,D) as from enzyme crystal structure (PDB id: 4ruh).

Figure 4

Structure of the most abundant substrates of human serum carnosinase.

Figure 5

LIGPLOT diagram of mouse carnosinase 2 complexed with zinc and bestatin as from enzyme crystal structure (PDB id: 2zog).

Figure 6

Structure and configuration of the main substrate (i.e., carnosine) and of the competitive inhibitors of human serum carnosinase.

Figure 7

Structure of some carnosinase-resistant compounds with in vitro properties mimicking carnosine.

Figure 8

Structure–activity relationship chart for development of carnosine derivatives. Groups impacting only on carnosinase binding have a green glow. Groups impacting only on absorption (PepT1 recognition) have a purple glow. Groups impacting on both activity and carnosinase binding have a blue glow. Groups impacting on activity, absorption and carnosinase binding have an orange glow.