Función e importancia clínica de la enzima lisil-oxidasa / Role and clinical significance of the lysyl oxidase enzyme / Funções e importância clínicas da enzima lisil-oxidase

La lisil-oxidasa (LOX) es una quinoenzima que contiene cobre y lisil-tirosilquinona como cofactor. Esta amino-oxidasa actúa en la catálisis de la desaminación oxidativa de residuos de lisina en los precursores del colágeno y de elastina. Anteriormente se ha informado sobre su biosíntesis, sus propiedades catalíticas y mecanismo de reacción, cofactores e inhibidores, así como la expresión y respuesta a diversos efectores celulares. En este trabajo se analizan las funciones e implicancias clínicas de LOX ya que sus niveles aumentan en muchas enfermedades fibróticas y en algunos tumores, con lo que promueven metástasis, mientras que la expresión de la enzima está disminuida en enfermedades que involucran un deterioro en el metabolismo del cobre. LOX tiene funciones paradójicas en cáncer puesto que actúa tanto en la supresión como en la promoción tumoral. Se plantea su rol en la aterogénesis y la disfunción endotelial, en trastornos oculares, fibrosis, enfermedades iatrogénicas, regeneración ósea y aumento del riesgo de enfermedades cardiovasculares, entre otras. Se encaran los últimos avances referidos a la acción proangiogénica del cobre y las funciones de la proteína precursora de LOX, cuyos niveles de expresión están asociados con diversos tipos de cáncer.

Lysyl oxidase (LOX) is a copper-containing quinoenzyme, having lysyl-tyrosyl-quinone as cofactor. This amino oxidase catalyzes the oxidative deamination of lysine residues in collagen and elastin precursors. Its biosynthesis, catalytic properties and reaction mechanism, cofactors and inhibitors as well as expression and response to various cellular effectors have previously been reported. In the present paper, functions and clinical implications of LOX are analyzed, since LOX levels are increased in many fibrotic diseases, and in some tumors promoting metastasis, whereas the expression of the enzyme is decreased in diseases involving deterioration in copper metabolism. LOX shows paradoxical roles in cancer both suppressing and promoting tumors. The role of LOX in atherogenesis and endothelial dysfunction, eye disorders, fibrosis, iatrogenic diseases, bone regeneration, and increased risk of cardiovascular disease, among others, are addressed. Recent developments related to the proangiogenic action of copper and functions of LOX precursor protein, whose expression levels are associated with various cancers, are discussed.

A lisil oxidase (LOX) é uma quinoenzima contendo cobre e lisil-tirosil-quinona como cofator. Esta amino oxidase atua na catálise da desaminação oxidativa de resíduos de lisina de precursores de colágeno e elastina. Anteriormente foi informado sobre sua biossíntese, suas propriedades catalíticas e mecanismo de reação, cofatores e inibidores, bem como a expressão e resposta a vários efetores celulares. Neste trabalho as funções e implicações clínicas de LOX são analisadas visto que seus níveis aumentam em muitas doenças fibróticas e em alguns tumores promovendo metástases, enquanto que a expressão da enzima está reduzida em doenças que envolvem deterioração no metabolismo do cobre. LOX tem funções paradoxais em câncer, uma vez que atua tanto na supressão quanto na promoção tumoral. Discute-se ser papel na aterogênese e disfunção endotelial, distúrbios oculares, fibrose, doenças iatrogênicas, regeneração óssea e aumento do risco de doença cardiovascular, dentre outras. São encarados os últimos avanços associados com a ação pró-angiogênica do cobre e as funções da proteína precursora de LOX, cujos níveis de expressão estão associadas com vários tipos de câncer.

Lisil-oxidasa (LOX) y proteinas tipo LOX: rol de amino-oxidasas, propiedades moleculares y cataliticas / Lysyl oxidase (LOX) and LOX-like proteins: role of amino-oxidases, molecular and catalytic properties / Lisil-oxidase (LOX) e proteinas tipo LOX: papel da amino-oxidases, propriedades moleculares e catalíticas

Las amino-oxidasas pertenecen a dos grupos de proteinas: flavoenzimas y quinoenzimas. La lisil-oxidasa (LOX) es una quinoenzima que contiene cobre y lisil-tirosil-quinona como cofactor. Los niveles de LOX aumentan en muchas enfermedades fibroticas y en algunos tumores promoviendo metastasis, mientras que la expresion de la enzima esta disminuida en enfermedades que involucran un deterioro en el metabolismo del cobre. Se discute el rol de LOX como amino-oxidasa en la catalisis de la desaminacion oxidativa de residuos de lisina en los precursores del colageno y de elastina, y la participacion de los restantes miembros de esta familia genica: LOXL1, LOXL2, LOXL3 y LOXL4, asi como sus propiedades moleculares. Se analizan su biosintesis, sus propiedades cataliticas y mecanismo de reaccion, cofactores e inhibidores y la expresion y respuesta a diversos efectores celulares.

Amino-oxidases belong to two groups of proteins: flavoenzymes and quinoenzymes. Lysyl oxidase (LOX) is a copper-containing quinoenzime, having lysyl-tyrosyl-quinone as cofactor. LOX levels are increased in many fibrotic diseases, and in some tumors promoting metastasis, while the enzyme expression is decreased in diseases that involve deterioration in copper metabolism. The role of LOX as amino oxidase in catalyzing the oxidative deamination of lysine residues in precursors of collagen and elastin is discussed, as well as the participation of other members of this gene family: LOXL1, LOXL2, LOXL3, and LOXL4, and their molecular properties. The biosynthesis, catalytic properties and reaction mechanism, cofactors and inhibitors, and the expression and response to various cellular effectors are analyzed.

As amina oxidases pertencem a dois grupos de proteínas: flavoenzimas e quinoenzimas. A lisil-oxidase (LOX) é uma quinoenzima contendo cobre e lisil-tirosil-quinona como cofator. Os níveis da enzima LOX aumentam em muitas doenças fibróticas e em alguns tumores promovendo metástase, enquanto que a expressão da enzima está reduzida em doenças que envolvem a deterioração no metabolismo do cobre. Discute-se o papel de LOX como amina oxidase na catálise a desaminação oxidativa de resíduos de lisina de precursores de colágeno e de elastina, e a participação dos outros membros desta família gênica: LOXL1, LOXL2, LOXL3 e LOXL4, bem como as suas propriedades moleculares. A sua biossíntese, as suas propriedades catalíticas e mecanismo de reação, cofatores e inibidores e a expressão e resposta a diversos efetores celulares são analisados.

Antimicrobial Profile of Selected Snake Venoms and Their Associated Enzymatic Activities.

Aims: To investigate the antiviral and antibacterial profile of several crude snake venoms and to assess some of their enzymatic activities. Methodology: The antiviral activities of Naja haje, Bitis arietans, Naja nigricollis and Echis carinatus snake venoms were investigated against Herpes simplex virus type1, Rift valley fever virus and Vesicular stomatitis virus using the end point of cytopathic effect method. Antibacterial activities of Bitis arietans, Cerastes cerastes, Echis carinatus, Vipera lebetina, Naja naja, Pseudechis australis, Naja nigricollis and Naja haje venoms were examined against Staphylococcus aureus, Escherichia coli, Salmonella typhimurium and Pseudomonas aeruginosa using disc diffusion method. Microdilution method was used to determine the venom's minimum inhibitory concentration. L-amino acid oxidase and phospholipase A2 activities of crude venoms were evaluated using enzymatic assays. Results: Naja nigricollis, Bitis arietans and Echis carinatus snake venoms exhibited significant antiviral activities against all test viruses, except for N. haje treated cells. The mean depletion of viral infectivity titer of venom pretreated cells was higher than its depletion post viral infection for all three venoms showing antiviral activities. Naja nigricollis exhibited the highest antiviral activity against test viruses and recorded a mean depletion of viral infectivity titer in venom pretreated cells of 3.8 log (10) / ml , 3.2 log (10) / ml and 2.5 log (10) / ml for HSV-1, RVFV and VSV, respectively. Pseudechis australis, followed by Naja naja and Naja nigricollis venoms, showed the highest inhibitory activity against test bacteria with inhibition zones ranging from 11-17 mm, 8-14 mm and 8-13 mm, respectively. Minimum inhibitory concentrations of test venoms against different bacterial strains ranged from 156 μg / ml to 1.25 mg / ml. Maximum L- amino oxidase activity was detected in Naja naja, Cerastes cerastes and Pseudechis australis. The highest Phospholipase A2 activity was identified in Bitis arietans, Pseudechis australis, Naja naja and Naja nigricollis. Conclusion: It can be concluded that snake venoms or their bioactive derivatives can be promising therapeutic agents against some microbial infections. Further investigations will be carried out for purification and more characterization of the biologically active components in snake venoms.

Antimicrobial activity of an L-amino acid oxidase isolated from Bothrops leucurus snake venom

Some snake venom proteins present enzymatic activities, such as L-amino acid oxidase (LAAO). The aim of this paper was to investigate the effect of Bothrops leucurus total venom (BleuTV) and its fraction LAAO (BleuLAAO) on bacteria, yeast, and promastigote forms of Leishmania amazonensis and Leishmania chagasi, and epimastigote forms of Trypanosoma cruzi. BleuTV was isolated with a Protein Pack 5PW® (Waters Corporation, USA), and several fractions were obtained. BleuLAAO was purified to high molecular homogeneity, and its N-terminal amino acid sequence shared a high degree of amino acid conservation with other LAAOs. BleuTV inhibited Staphylococcus aureus growth in a dose-dependent manner, with a minimum inhibitory concentration (MIC) of 25 ìg/mL, which corresponded to its minimum lethal concentration (MLC). BleuTV also inhibited the growth of promastigote forms of L. chagasi and L. amazonensis, with respective IC50 values of 1.94 ìg/mL and 5.49 ìg/mL. Furthermore, it repressed T. cruzi growth with an IC50 of 1.14 ìg/mL. However, BleuLAAO did not inhibit the growth of the microorganisms studied and was not toxic to macrophages. BleuTV had low toxicity against macrophages at the concentrations studied. In conclusion, whole venom from Bothrops leucurus inhibited the growth of some microorganisms, including S. aureus, Leishmania sp., and T. cruzi.