M2-Изоформа пируваткиназы PKM: фундаментальные и трансляционные аспекты в контексте молекулярной диагностики злокачественных опухолей человека

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Аннотация

M2-изоформа гликолитического фермента пируваткиназы PKM (PKM2) является одним из центральных фокусов внимания современных исследований в области онкометаболизма. Она представляет собой высокоадаптивный метаболический мастер-регулятор, осуществляющий переключение между режимами генерации энергии за счёт высокоэффективной конверсии фосфоенолпирувата в пируват с образованием ATP и накопления метаболического ресурса в виде гликолитических интермедиатов, включающихся в процессы биосинтеза аминокислот, нуклеотидов и жирных кислот. Характеризующаяся высокой функциональной и регуляторной пластичностью PKM2 представляет собой идеальный инструмент для метаболической адаптации PKM2-экспрессирующих клеток, в особенности клеток злокачественных опухолей, демонстрирующих резко аномальные метаболические потребности. Молекулярные дактилограммы PKM2-зависимой метаболической адаптации, такие как гиперэкспрессия PKM2, сдвиг равновесия тетрамер/димер PKM2 в сторону последнего и его выход в циркуляцию, а также иммунный ответ против PKM2 могут служить биомаркерами широкого спектра злокачественных новообразований. Настоящий обзор посвящён анализу возможностей молекулярной дактилографии PKM2-зависимой метаболической адаптации для диагностики злокачественных опухолей человека в контексте фундаментальных аспектов биологии PKM2 и исторических и современных воззрений на процесс PKM2-зависимой метаболической адаптации.

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П. В. Белоусов

Институт молекулярной биологии им. В.А. Энгельгардта РАН

Автор, ответственный за переписку.
Email: belousp@gmail.com
Россия, Москва

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2. Рис. 1. Схематичное изображение гликолиза (зеленые прямоугольники) и точек его пересечения с другими биохимическими путями (пунктирные линии). 1,3-BPG – 1,3-бисфосфоглицерат, 2PG – 2-фосфоглицерат, 3PG – 3-фосфоглицерат, ALDO – альдолаза, CS – цитратсинтаза, DHAP – дигидроксиацетонфосфат, ENO – енолаза, F1,6BP – фруктоза-1,6-бисфосфат, F6P – фруктоза-6-фосфат, G3P – глицеральдегид-3-фосфат, G6P – глюкоза-6-фосфат, GAPDH – глицеральдегид-3-фосфатдегидрогеназа, GPI – глюкоза-6-фосфатизомераза, HK – гекcокиназа, LDH – лактатдегидрогеназа, PDH – пируватдегидрогеназа, PEP – фосфоенолпируват, PFK – фосфофруктокиназа, PGK – фосфоглицераткиназа, PGM – фосфоглицератмутаза, TPI – триозофосфатизомераза, ПФШ – пентозофосфатный шунт, ЭТЦ – электрон-транспортная цепь

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3. Рис. 2. Структурная и функциональная пластичность PKM2. Наиболее изученные аллостерические регуляторы PKM2 перечислены в нижней части рисунка в виде облаков терминов. DASA – N,N′-диарилсульфонамид, F1,6BP – фруктоза-1,6-бисфосфат, PEP – фосфоенолпируват, SAICAR – фосфорибозиламиноимидазолсукцинокарбоксамид, ПФШ – пентозофосфатный шунт

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