Mammalian alpha-L-fucosidases are a ubiquitous group of relatively large multimeric lysosomal glycosidases involved in the degradation of a diverse group of naturally-occurring fucoglycoconjugates. These enzymes are closely related structurally as indicated by immunochemical cross-reactivity and cloning studies. Mammalian fucosidases are sialoglycoproteins and the carbohydrate, particularly sialic acid, contributes to producing multiple isoforms which can differ in various species as well as in different tissues within a given species. alpha-L-Fucosidases exhibit maximal activity at pH values between 4 and 7, have similar kinetic properties with synthetic substrates (PNP-fucoside and 4-MU-fucoside), and exhibit broad substrate specificity on natural substrates. Numerous linkages (alpha 1-2, alpha 1-3, alpha 1-4, alpha 1-6), primarily to galactose and N-acetylglucosamine, can be hydrolyzed but preference is often seen for small mol. wt water-soluble substrates with fucose in alpha 1-2 linkage to galactose. The importance of alpha-L-fucosidase in mammalian metabolism is evidenced by deficiency or absence of its enzymatic activity leading to a fatal genetic disease, at least in humans and English Springer Spaniels.

Mammalian α-l-fucosidases

Molecular nosology of heritable disorders of connective tissue.

The tumor suppressor p53 functions by inducing the transcription of a collection of target genes. We previously attempted to identify p53 target genes by microarray expression and ChIP-sequencing analyses. In this study, we describe a novel p53 target gene, FUCA1, which encodes a fucosidase. Although fucosidase, α-l-1 (FUCA1) has been reported to be a lysosomal protein, we detected it outside of lysosomes and observed that its activity is highest at physiological pH. As there is a reported association between fucosylation and tumorigenesis, we investigated the potential role of FUCA1 in cancer. We found that overexpression of FUCA1, but not a mutant defective in enzyme activity, suppressed the growth of cancer cells and induced cell death. Furthermore, we showed that FUCA1 reduced fucosylation and activation of epidermal growth factor receptor, and concomitantly suppressed epidermal growth factor signaling pathways. FUCA1 loss-of-function mutations are found in several cancers, its expression is reduced in cancers of the large intestine, and low FUCA1 expression is associated with poorer prognosis in several cancers. These results show that protein defucosylation mediated by FUCA1 is involved in tumor suppression.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/cas.12933

Novel p53 target gene FUCA1 encodes a fucosidase and regulates growth and survival of cancer cells

Structure and sequence of the human α-l-fucosidase gene and pseudogene

cDNA clones for alpha-L-fucosidase were isolated from a rat liver lambda gt11 expression library by using both monospecific polyclonal antibodies against the affinity-purified enzyme and biotinylated rat liver fucosidase cDNA sequences as probes. The largest clone, lambda FC9, contained a 1522 bp full-length cDNA insert (FC9) that encoded the 434-amino acid-residue subunit (Mr 50439) of rat liver alpha-L-fucosidase. A putative signal peptide 28 amino acid residues in length preceded the sequence for the mature protein. In addition, FC9 specified for 11 nucleotide residues of 5' untranslated sequence, 78 nucleotide residues of 3' untranslated sequence and a poly(A) tail. The deduced amino acid sequence from FC9 in conjunction with the experimentally determined N-terminus of the mature enzyme suggested that rat liver fucosidase did not contain a pro-segment. However, there was the possibility of limited N-terminal processing (one to five amino acid residues) having occurred after removal of the predicted signal peptide. Amino acid sequences deduced from FC9 were co-linear with amino acid sequences measured at the N-terminus of purified fucosidase and on two of its CNBr-cleavage peptides. An unusual aspect of rat liver alpha-L-fucosidase protein structure obtained from the FC9 data was its high content of tryptophan (6%). The coding sequence from FC9 showed 82% sequence identity with that from a previously reported incomplete human fucosidase sequence [O'Brien, Willems, Fukushima, de Wet, Darby, DiCioccio, Fowler & Shows, (1987) Enzyme 38, 45-53].

/pdf/isolation-and-sequence-analysis-of-a-cdna-encoding-rat-liver-2z6h14wypg.pdf

Isolation and sequence analysis of a cDNA encoding rat liver α-l-fucosidase

Fucosidosis is an autosomal recessive lysosomal storage disorder characterized by progressive neurological deterioration and mental retardation. The disease results from deficient activity of alpha-L-fucosidase (E.C.3.2.1.51), a lysosomal enzyme that hydrolyzes fucose from fucoglycoconjugates. In an attempt to identify the mutation(s) that result(s) in fucosidosis, we performed Southern blot analysis of the structural gene encoding alpha-L-fucosidase (FUCA 1) in 23 patients affected with fucosidosis. In five patients Southern blot analysis showed obliteration of an EcoRI restriction site in the open reading frame of FUCA 1 encoding mature alpha-L-fucosidase. This abnormality was not observed in 80 controls, and it may be the basic defect responsible for fucosidosis in these patients. Both patients with the severe type I form of fucosidosis and patients with the less severe type II were shown to be homozygous for this presumed mutation. In the remaining 18 patients the EcoRI site obliteration, major-gene deletions, or insertions were not detected. This suggests that at least two different mutations are involved in fucosidosis. The heterogeneity found at the DNA level was not present at the protein level, as all fucosidosis patients investigated had low fucosidase protein (less than 6% of normal) and negligible fucosidase activity in fibroblasts and lymphoblastoid cell lines.

Identification of a mutation in the structural alpha-L-fucosidase gene in fucosidosis.

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Identification of a mutation in the structural alpha-L-fucosidase gene in fucosidosis.