透明質酸脢是水解透明質之酵素，廣泛分佈於自然界，存在於哺乳類動物、昆蟲、水蛭及細菌中，本論文首先在第一、二章對透明質酸脢的分類、來源、活性分析法、生物化學特性、觸媒反應機制、及其在醫藥、生物產業上之應用做了詳盡、廣泛的文獻回顧。第三章中以基因工程的方法將細菌Streptococcus pyrogenes之噬菌體H4489A所含之透明質酸裂解脢(hyaluronate lyase)基因在大腸桿菌中表現，透明質酸裂解脢是屬於透明質酸脢之一種，裂解透明質酸產生出具不飽和鍵之多醣，重組透明質酸裂解脢經固定金屬層析後，再以離子交換層析純化，所得之純化酵素分子量約40 KDa，最佳反應pH、溫度分別在5.5及37oC。在第四章中探討多種二價金屬離子及界面活性劑對此重組透明質酸裂解脢活性之影響，鎂離子可活化但銅、鎳、鈷離子完全抑制其活性。其反應動力學可以Michaels-Menten模式來描述，其中動力學參數Km為0.44mg/ml，最大反應速率Vm為0.20 贡mol/ml/min，變性溫度在46 oC左右。此外也以CD光譜在尿素及鹽酸胍 (guanidine hydrochloride) 等變性劑的作用下研究透明質酸裂解脢之二級結構。在第五章中討論裂解脢裂解透明質酸所產生出具不飽和鍵之多醣，經陰離子交換層析分離後可得到20種片段不同之不飽和多醣，此不飽和多醣對四種腫瘤細胞具有輕微之細胞毒性，但有抗脂質(lipid)氧化的能力，及清除自由基的活性。第六章中將探討人類精子細胞膜表面之透明質酸水解脢(rhuPH20) 的異源表現，以嗜甲基酵母菌(Pichia pastoris)為宿主細胞，所使用之調控系統為組成性之GAP表現系統，經抗His-tag及PH20之抗體檢驗，證實rhuPH20可成功地被嗜甲基酵母菌所表現出來，培養基之碳源對其表現量有很大的影響，其中以甘油為碳源可得最佳之表現量，經Zymography分析胞外表現之rhuPH20證實其具有活性，在native及reducing條件所測得其分子量分別為120 KDa及56 KDa，推論嗜甲基酵母菌所表現之rhuPH20以dimer型式存在。

Hyaluronidases represent a group of glycosidases, which mainly degrade hyaluronan, a linear, non-sulfated polysaccharide composed of repeating disaccharide units [D-glucuronic acid (1-β-3) N-acetyl-D-glucosamine (1-β-4)]n. They are widely distributed in nature, being found in mammals, insects, leeches and bacteria. Chapters 1 and 2 of this PhD thesis summarizes the past, current research, and state of the art on their classification, sources, activity assays, bio-physical and chemical properties, crystal structural features and its catalytic mechanism. Special emphasis is given to the importance role of that type of enzymes in biotechnological processes, as well as its medicinal and bio-industrial applications.

In first experimental task (Chapter 3), hyaluronate (HA) lyase of Streptococcus pyogenes bacteriophage H4489A, was heterologously expressed in Escherichia coli and purified using immobilized affinity, followed by ion exchange chromatography. Culture extraction and all purification steps were checked by SDS-PAGE electrophoresis. Also, the enzyme purity and activity was detected by zymography. The phage HA lyase activities were estimated by colorimetric and turbidity assays.

Chapter 4 discusses the detailed experimental results on the characterization of hyaluronate (HA) lyase of Streptococcus pyogenes bacteriophage H4489A. The effects of pH, temperature, metal ions (Ca (II), Ni (II), Zn (II), Co (II), Cu (II), and Mg (II)), and surfactants (Triton X-100, Tween 20) on the activity of the purified phage HA lyase were studied. The purified homogeneous preparation of HA lyase has a molecular mass of 40 kDa. The optimum enzymatic activity was achieved at pH ~ 5.5 and 37oC, and the enzyme was stable at pH from 4 to 7 and temperature range from 25 to 45 oC. The enzymatic activity toward HA, was vaguely enhanced by Mg+2, slightly inhibited by Ca+2, Triton X-100, and Tween 20, strongly inhibited by Zn+2, and completely inhibited by Cu+2, Ni+2, Co+2 and sodium dodecyl dulfate. Michaelis-Menten kinetic model determined Michaelis constant of 0.44 mg/ml, maximal velocity of 0.20 μmolml-1min-1. It showed that bacteriophage HA lyase degraded the HA efficiently. Light scattering dynamic measurements determined the denaturation temperate of HA lyase of about 46oC. Circular dichromism and UV-visible absorption spectroscopy estimated the changes in secondary structure of native and denatureated HA lyase. This characterization data provided an important basis for the exploitation of HA lyases.

In the third experimental task (Chapter 5), the recombinant hyaluronate lyase (EC 4.2.2.1, HA lyase) of Streptococcus pyogenes bacteriophage H4489A was applied to digest hyaluronan producing unsaturated hyaluronan oligomers. The resulted unsaturated hyaluronan oligomers were purified and subjected to anion-exchange high performance chromatography. The cytotoxic activities of naturally hyaluronan, hyaluronate lyase and unsaturated hyaluronan oligomers were tested and evaluated against HEp-2 (human laryngeal carcinoma), Daoy (human medulloblastoma), MCF-7 (human breast adenocarcinoma), and WiDr (human colon adenocarcinoma) tumor cell lines. It was shown that, the purification and anion-exchange HPLC separation method employed here allowed the production and purification of about 20 HA oligomers. Among the compounds tested for its cytotoxic activity, unsaturated HA oligomers exhibited a moderate cytotoxic activity against all four tumor cell lines, while the HA lyase shows a weak cytotoxic activities against the tumor cell lines. In contrast, naturally HA was not effective as it reveals non-significant cytotoxic effects to all tumor cell types. The experimental data revealed that, both naturally HA and unsaturated HA oligomers exhibited a reasonable antilipid oxidation activity. However, unsaturated HA oligomers gives strong antilipid oxidation activities than naturally HA. Quite the opposite, HA lyase displayed weak antilipid oxidation activities. In this context, HA oligomers exhibited a strong radical scavenging activity than HA, in which HA shows a moderate activity. While, it was observed that, HA lyase shows weak radical scavenging activity. It is worth mentioning that, there is slightly increment of antioxidation activities of naturally HA, native HA lyase protein, unsaturated HA oligomers with the increase of their concentrations.

In Chapter 6, a novel recombinant human hyaluronidase (rhuPH20) was expressed in Pichia pastoris. The recombinant human PH-20 was detected by anti His tag and anti PH-20 –antibody under reducing and non-reducing conditions. It was found that, the active recombinant human PH-20 (rhuPH20) could be successfully and its expression level was affected by the carbon sources employed in the culture media. The maximum cell growth was achieved by using dextrose and sorbitol as carbon sources. The level of rhuPH-20 expression reached the optimum when glycerol was used as the carbon source. The molecular weight of expressed rhPH-20 confirmed using western blotting analysis and zymoraphy was found to be around 120 kDa in the native condition, while it was detected of about 56 kDa under reducing condition. Evidently, rhPH-20 was expressed in a dimer form in Pichia pastoris.

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