Assuntos
Pesquisa Biomédica/história , Cardiologia/história , Insuficiência Cardíaca/história , Diester Fosfórico Hidrolases/história , Escolha da Profissão , AMP Cíclico/história , AMP Cíclico/metabolismo , Insuficiência Cardíaca/enzimologia , Insuficiência Cardíaca/fisiopatologia , História do Século XX , História do Século XXI , Humanos , Isoenzimas , Diester Fosfórico Hidrolases/metabolismo , Sistemas do Segundo MensageiroRESUMO
Spiders of the genus Loxosceles, popularly known as Brown spiders, are considered a serious public health issue, especially in regions of hot or temperate climates, such as parts of North and South America. Although the venoms of these arachnids are complex in molecular composition, often containing proteins with distinct biochemical characteristics, the literature has primarily described a family of toxins, the Phospholipases-D (PLDs), which are highly conserved in all Loxosceles species. PLDs trigger most of the major clinical symptoms of loxoscelism i.e., dermonecrosis, thrombocytopenia, hemolysis, and acute renal failure. The key role played by PLDs in the symptomatology of loxoscelism was first described 40 years ago, when researches purified a hemolytic toxin that cleaved sphingomyelin and generated choline, and was referred to as a Sphingomyelinase-D, which was subsequently changed to Phospholipase-D when it was demonstrated that the enzyme also cleaved other cellular phospholipids. In this review, we present the information gleaned over the last 40 years about PLDs from Loxosceles venoms especially with regard to the production and characterization of recombinant isoforms. The history of obtaining these toxins is discussed, as well as their molecular organization and mechanisms of interaction with their substrates. We will address cellular biology aspects of these toxins and how they can be used in the development of drugs to address inflammatory processes and loxoscelism. Present and future aspects of loxoscelism diagnosis will be discussed, as well as their biotechnological applications and actions expected for the future in this field.
Assuntos
Fosfolipase D/história , Diester Fosfórico Hidrolases/história , Venenos de Aranha/história , Animais , Catálise , História do Século XX , História do Século XXI , Humanos , Fosfolipase D/química , Fosfolipase D/farmacologia , Diester Fosfórico Hidrolases/química , Diester Fosfórico Hidrolases/farmacologia , Proteômica , Proteínas Recombinantes/farmacologia , Picada de Aranha/diagnóstico , Picada de Aranha/tratamento farmacológico , Picada de Aranha/enzimologia , Venenos de Aranha/química , Venenos de Aranha/farmacologiaRESUMO
My initial research experience involved studying how bacteria synthesize nucleotide sugars, the donors for the formation of cell wall polysaccharides. During this time, I became aware that mammalian cells also have a surface coat of sugars and was intrigued as to whether these sugars might be arranged in specific sequences that function as information molecules in biologic processes. Thus began a long journey that has taken me from glycan structural analysis and determination of plant lectin-binding preferences to the biosynthesis of Asn-linked oligosaccharides and the mannose 6-phosphate (Man-6-P) lysosomal enzyme targeting pathway. The Man-6-P system represents an early example of a glycan serving as an information molecule in a fundamental cellular function. The remarkable advances in the field of glycobiology since I entered have uncovered scores of additional examples of oligosaccharide-lectin interactions mediating critical biologic processes. It has been a rewarding experience to participate in the efforts that have established a central role for glycans in biology.