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Abstract
The human genome contains six hyaluronidase-like genes. Three genes (HYAL1, HYAL2
and HYAL3) are clustered on chromosome 3p21.3, and another two genes (HYAL4 and PH-20/SPAM1)
and one expressed pseudogene (HYALP1) are similarly clustered on chromosome 7q31.3.
The extensive homology between the different hyaluronidase genes suggests ancient
gene duplication, followed by en masse block duplication, events that occurred before
the emergence of modern mammals. Very recently we have found that the mouse genome
also has six hyaluronidase-like genes that are also grouped into two clusters of three,
in regions syntenic with the human genome. Surprisingly, the mouse ortholog of HYALP1
does not contain any mutations, and unlike its human counterpart may actually encode
an active enzyme. Hyal-1 is the only hyaluronidase in mammalian plasma and urine,
and is also found at high levels in major organs such as liver, kidney, spleen, and
heart. A model is proposed suggesting that Hyal-2 and Hyal-1 are the major mammalian
hyaluronidases in somatic tissues, and that they act in concert to degrade high molecular
weight hyaluronan to the tetrasaccharide. Twenty-kDa hyaluronan fragments are generated
at the cell surface in unique endocytic vesicles resulting from digestion by the glycosylphosphatidyl-inositol-anchored
Hyal-2, transported intracellularly by an unknown process, and then further digested
by Hyal-1. The two beta-exoglycosidases, beta-glucuronidase and beta-N-acetyl glucosaminidase,
remove sugars from reducing termini of hyaluronan oligomers, and supplement the hyaluronidases
in the catabolism of hyaluronan.