KIAA1363-A Multifunctional Enzyme in Xenobiotic Detoxification and Lipid Ester Hydrolysis

Abstract

KIAA1363, annotated as neutral cholesterol ester hydrolase 1 (NCEH1), is a member of the arylacetamide deacetylase (AADAC) protein family. The name-giving enzyme, AADAC, is known to hydrolyze amide and ester bonds of a number of xenobiotic substances, as well as clinical drugs and of endogenous lipid substrates such as diglycerides, respectively. Similarly, KIAA1363, annotated as the first AADAC-like protein, exhibits enzymatic activities for a diverse substrate range including the xenobiotic insecticide chlorpyrifos oxon and endogenous substrates, acetyl monoalkylglycerol ether, cholesterol ester, and retinyl ester. Two independent knockout mouse models have been generated and characterized. However, apart from reduced acetyl monoalkylglycerol ether and cholesterol ester hydrolase activity in specific tissues and cell types, no gross-phenotype has been reported. This raises the question of its physiological role and whether it functions as drug detoxifying enzyme and/or as hydrolase/lipase of endogenous substrates. This review delineates the current knowledge about the structure, function and of the physiological role of KIAA1363, as evident from the phenotypical changes inflicted by pharmacological inhibition or by silencing as well as knockout of KIAA1363 gene expression in cells, as well as mouse models, respectively.

Keywords: KIAA1363; arylacetamide deacetylase-like 1; lipid metabolism; neutral cholesterol ester hydrolase 1; xenobiotics.

Figure 1

Gene organization of NCEH1/Nceh1. Gene organization of the human NCEH1 (A) and murine Nceh1 (B). Open boxes (white) represent non-coding 5′ and 3′ nucleotide sequences (ncds). Closed boxes (black) represent exons that are separated by intron stretches, represented by interconnecting lines. Lengths of non-coding and coding sequences (cds) are indicated.

Figure 2

Transcript variants and protein isoforms of human and murine Nceh1. (A) The human NCEH1 gene transcribes into 4 different transcript variants (TV) generated by alternative splicing or translation start codon usage ranging from 4307 to 4560 bp. Transcript variants vary in the 5′ and 3′ untranslated region (UTR) and coding sequence (CDS). The murine Nceh1 gene transcribes into a single 4394 bp long mRNA. (B) Human protein isoform A consists of 416 amino acids (aa). Isoform B is lacking 8 aa (position 123–130), leading to a shorter 408 aa protein. Isoform C is lacking 141 aa at the N-terminus, leading to the shortest protein consisting of 275 aa. The murine Nceh1 gene encodes for a single protein isoform consisting of 408 aa.

Figure 3

Domain organization of murine KIAA1363. Schematic representation of murine KIAA1363, with domain boundaries indicated. Single amino acids (aa) and sequences of specific functions are depicted. The α/β-hydrolase fold is colored orange. The area of the carboxylesterase domain is hatched. PCSK, pro-protein convertases subtilisin/kexin type serine protease; TMD, transmembrane domain.

Figure 4

Chlorpyrifos oxon metabolization catalyzed by KIAA1363. Red stars indicate the bond that is hydrolyzed.

Figure 5

Catalyzing of 2-acetyl monoalkylglycerol ether hydrolysis by KIAA1363. Red stars indicate the bond that is hydrolyzed.

Figure 6

Cholesterol ester hydrolysis catalyzed by KIAA1363. Red stars indicate the bond that is hydrolyzed.

Figure 7

Retinyl ester hydrolysis catalyzed by KIAA1363. Red stars indicate the bond that is hydrolyzed.