A comprehensive review on microbial hyaluronan-degrading enzymes: from virulence factors to biotechnological tools

Abstract

Hyaluronan (HA), a natural high molecular weight polysaccharide, has extensive applications in cosmetology and medical treatment. Hyaluronan-degrading enzymes (Hyals) act as molecular scissors that cleave HA by breaking the glucosidic linkage. Hyals are present in diverse organisms, including vertebrates, invertebrates and microorganisms, and play momentous roles in biological processes. In recent years, microbial Hyals (mHyals) have gained considerable attention for their exceptional performance in the production and processing of HA. Moreover, the applications of mHyals have been greatly extended to various biomedical fields. To explore the potential applications of mHyals, a thorough comprehension is imperative. In this context, this review systematically summarizes the sources, structures, mechanisms and enzymatic properties of mHyals and discusses their biological functions in host invasion, disease development, and regulation of intestinal flora. Furthermore, versatile applications inspired by their biological functions in medicine development, molecular biology, and industrial biotechnology are comprehensively reviewed. Finally, prospects are presented to emphasize the importance of exploration, expression and characterization of mHyals and the necessity of excavating their potential in biotechnological fields.

Keywords: Anti-bacteria; Cancer therapy; Disease development; Host invasion; Hyaluronan degradation; Hyaluronan detection; Hyaluronan lyase; Hyaluronan-degrading enzymes; Hyaluronidase.

Fig. 1

Phylogenetic analysis of mHyals. The phylogram was generated using the neighbor-joining algorithm implemented in MEG6 software and visualized by the tvBOT tool (Xie et al. 2023). Different clades and families are distinguished by distinct colors, and column heights represent sequence lengths

Fig. 2

Three-dimensional structures of mHyals. a Structures of HA lyases from S. pneumoniae (left, PDB: 1LOH) and S. agalactiae (right, PDB: 1LXM) in complex with HA6, respectively. b Electrostatic potential distribution in the catalytic cleft of 1LXM. c Structure arrangement of the catalytic triad and HA6 substrate in the cleft of 1LXM. d Structures of HylP1 from S. pyogenes SF370 phage (PDB: 2C3F). e Structure of TSβH region of 2C3F. f Electrostatic potential distribution at the concave groove of 6X3M in complex with HA8

Fig. 3

The tertiary structures of CBM70 (PDB entry 4D0Q). a The solvent-accessible surface of CBM70 is colored by electrostatic potential. b The magnified section shows the putative binding site of the CBM70 in the binding pocket

Fig. 4

Biological functions of mHyals

Fig. 5

Function-inspired biotechnological applications of mHyals. a Applications of mHyals in diagnosis and treatment of bacteria. The mHyals are employed as antibacterial agents to disrupt biofilms. Additionally, mHyals can serve as reporter molecules for detection of bacterial infections. When interaction with the inner walls of the channels, mHyals impede the difussion of electroactive ions, leading to a reduction in voltammetric signal and thereby enabling differential pulse voltammetry-based detection of bacterial infections. b Applications of mHyals in tumor therapies and drug delivery. Engineered strains expressing mHyal can remodel the tumor stroma, synergistically enhancing the penetrability of anticancer agents and inducing tumor resolution. Unsaturated O-HAs metabolized by mHyals inhibits the growth, migration and invasion of cancer cells through disruption of Erk1/2 activation and RhoA expression. Moreover, mHyals specifically induce rupture of the drug delivery system, triggering the release of anti-cancer drugs. c mHyals act as scissors for HA depolymerization and functional oligo HA preparation. d mHyals facilitate DNA transfer in encapsulated cells. e CBM of mHyals is incorporated into lateral flow immunoassay for the identification of HA. The mobility of CBM exhibit a gradual decline in correlation with the increase in HA concentration within the samples. As the concentration of HA increases, there is a progressive reduction in the intensity of the T line, which could be completely abolished at excessively elevated levels of HA