Трансгидрогеназная активность митохондриального Комплекса I и его нуклеотид-связывающие центры тема диссертации и автореферата по ВАК РФ 03.00.04, кандидат биологических наук Захарова, Наталья Владимировна

• Захарова, Наталья Владимировна
• кандидат биологических наук
• 2000

Оглавление диссертации кандидат биологических наук Захарова, Наталья Владимировна

СПИСОК СОКРАЩЕНИЙ

ВВЕДЕНИЕ

ОБЗОР ЛИТЕРАТУРЫ

1. Структура протон-транслоцирующих

ЛАОНгхинон оксидоредуктаз

1.1 Субъединицы

Субъединичный состав митохондриальных и бактериальных ферментов Субкомплексы

Ассоциация субъединиц в процессе сборки

Комплекса I Происхождение субъединиц и эволюция

Комплекса I МАБН-дегидрогеназы, нетранслоцирующие протоны

1.2 Редокс компоненты

Железо-серные центры Хиноны

2. Каталитические свойства митохондриальной

NADH:yбиxинoн оксидоредуктазы

2.1 Препараты ЫАБН-дегидрогеназы СМЧ

Комплекс I БР

2.2 Реакции, катализируемые Комплексом I ЫАБН-оксидазная реакция

- Дыхательный контроль

- Обратимая деактивация Комплекса I Обратный перенос электронов

Окисление ЫАБН искусственными акцепторами электронов

- Аналоги и гомологи убихинона

- Феррицианид и гексаминорутений Генерация супероксид аниона Трансгидрогеназная реакция

- Комплекс I

- Н^-трансгидрогеназа

2.3 Транслокация протонов

2.4 Ингибиторы Комплекса I

Ингибиторы центров связывания нуклеотидов и начальных этапов переноса электронов

- NAD+, NADH, ADP-рибоза и их производные

- Рейн

- Тинопалы 42 Ингибиторы восстановления хинонов

- Ротенон

- Пиерицидин А

- Ацетогенины

- Антибиотики миксобактерий

- Другие ингибиторы 45 3. Активный центр NADH:y6nximoH оксидоредуктазы

3.1 Центры связывания нуклеотидов 47 Субъединица 51 кДа 47 Субъединица 39 кДа 48 Субъединицы, метящиеся фотоаффинными аналогами нуклеотидов

3.2 Участие центров связывания нуклеотидов в реакциях Комплекса I 49 Указания на работу не менее двух центров связывания нуклеотидов 49 Подходы к определению количества субстрат-связывающих мест

МЕТОДЫ ИССЛЕДОВАНИЯ

1. Препаративные методы

1.1 Выделение митохондрий из сердца быка

1.2 Получение субмитохондриальных частиц (СМЧ)

1.3 Выделение ЫА1)Н:убихинон оксидоредуктазы из митохондрий

Промывание митохондрий

Получение препарата S1 (Комплексы I, II и III)

Получение препарата R4B (Комплексы I и III)

Выделение NADH:y6nxHHOH оксидоредуктазы

1.4 Фракционирование Комплекса I, выделение трехсубъединичного флавопротеина (FP)

1.5 Обработка СМЧ трипсином

1.6 Сопряжение СМЧ олигомицином

1.7 Получение APADH

2. Аналитические методы

2.1 Реакции, катализируемые препаратами

NADH-дегидрогеназы

NADH-оксидазная реакция, дыхательный контроль (ДК)

Сукцинат-зависимый обратный перенос электронов

DD трансгидрогеназная реакция

2.2 Определение концентрации APAD+ и NAD+

2.3 Преинкубация Комплекса I с NADH

2.4 Экстракция нуклеотидов 63 Экстракция NAD+ и флавинов хлорной кислотой 63 Экстракция флавинов трихлоруксусной кислотой (ТХУ) 63 Щелочная экстракция NADH

2.5 Регистрация Ар,н+

2.6 Кинетическое определение механизма бисубстратной реакции

Тройной комплекс и двойное замещение 65 Последовательность взаимодействия субстратов с ферментом в реакциях, протекающих с образованием тройного комплекса

РЕЗУЛЬТАТЫ

1. NADH:y6HXHHOH оксидоредуктаза и DD трансгидрогеназная активность СМЧ

2. Кинетический механизм DD трансгидрогеназной реакции, катализируемой NADH:y6nxnHOH оксидоредуктазой

2.1 СМЧ 70 NADH-»APAD+ реакция 70 APADH-»NAD+ реакция

2.2 Комплекс I

2.3 FP

2.4 Содержание связанных нуклеотидов в составе Комплекса I

3. Окисление и восстановление нуклеотидов в реакциях прямого и обратного переноса электронов, катализируемых Комплексом I

4. Влияние обратимых ингибиторов активного центра

Комплекса I на DD трансгидрогеназную реакцию

4.1 ADP-рибоза

4.2 Рейн

4.3 NAD+

4.4 Тинопалы (AMS-GX, 5BM-GX) 95 Влияние тинопалов на спектры поглощения

NADHhAPADH 96 Влияние AMS-GX и 5BM-GX на DD реакцию

Комплекса I

5. DD трансгидрогеназная реакция 1 и A|uH+

ОБСУЖДЕНИЕ

ВЫВОДЫ

Введение диссертации (часть автореферата) на тему «Трансгидрогеназная активность митохондриального Комплекса I и его нуклеотид-связывающие центры»

NADH:y6nxHHOH оксидоредуктаза (Комплекс I, NADH-дегидрогеназа, КФ 1.6.5.3) - чрезвычайно сложный компонент дыхательной цепи митохондрий. Фермент катализирует окисление NADH убихиноном, сопряженное с векторным переносом 4 протонов из матрикса митохондрий в межмембранное пространство. Комплекс I построен не менее чем из 41 субъединиц (общая молекулярная масса - порядка 1 ООО ООО Да) и содержит FMN, 5-7 железосерных кластеров и связанный убихинон.

Свойства нуклеотид-связывающего активного центра(ов) Комплекса I мало изучены. До последнего времени считалось общепринятым, что фермент имеет единственный центр специфичного связывания NADH и/или NAD+, ассоциированный с его 51 кДа флавин-содержащей субъединицей. Однако, ряд данных указывает на существование более чем одного центра связывания нуклеотидов в составе Комплекса I. Такие данные кратко суммированы ниже:

1) Fe-S кластеры фермента по-разному восстанавливаются при добавлении NADH или NADPH;

2) кинетика генерации супероксид-радикала характеризуется двумя значениями Кт как для NADH, так и для NADPH;

3) в зависимости от концентрации, NAD+ влияет как конкурентный или неконкурентный ингибитор по отношению к NADH;

4) фотоаффинные аналоги субстратов включаются в несколько субъединиц фермента;

5) сродство фермента к NAD+ и NADH в реакциях окисления NADH и А|Ын+-зависимого восстановления NAD+ убихиноном существенно различается;

6) ADP-рибоза конкурирует с NADH в прямой реакции и не влияет на обратный перенос электронов. 8

Таким образом, мы полагаем, что количество центров связывания нуклеотидов остается неизвестным. Способность Комплекса I катализировать трансгидрогеназную реакцию предоставляет одну из возможностей для изучения нуклеотид-связывающих свойств фермента. Кинетическое исследование этой бисубстратной реакции может служить, хотя и косвенным, но достаточно надежным инструментом для этой цели.

В настоящей работе в качестве инструмента исследования свойств активного центра(ов) Комплекса I была использована NADH—>АРАБ+ (3-ацетилпиридин аденин динуклеотид) трансгидрогеназная реакция, катализируемая тремя препаратами ЫАОН:дегидрогеназы: субмитохондриальными частицами (СМЧ), изолированным Комплексом I и его трехсубъединичным фрагментом БР. Полученные результаты позволяют считать, что фермент содержит не менее трех функционально значимых центров связывания субстратов-нуклеотидов.

ОБЗОР ЛИТЕРАТУРЫ

Заключение диссертации по теме «Биохимия», Захарова, Наталья Владимировна

выводы

1. Показано, что митохондриальная NADH.-убихинон оксидоредуктаза катализирует две NADH-»APAD+ (DD) трансгидрогеназные реакции, отличающиеся по скоростям, кинетическому механизму, сродству к субстратам и чувствительности к Ацн+

2. Установлено, что реакция 1 протекает по упорядоченному механизму с образованием тройного комплекса, с участием двух нуклеотид-связывающих центров. Оба центра входят в состав трехсубъединичного флавопротеина (FP). NADH является первым субстратом. Для реакции характерно двойное субстратное ингибирование при концентрациях субстратов, на порядок привышающих Кт. Реакция ингибируется при энергизации мембраны.

3. В DD реакции 1 восстановленный нуклеотид связывается в том же центре, что и в NADH-оксидазной реакции. Центр связывания окисленного нуклеотида в реакции 1 идентичен субстрат-связывающему центру в реакции обратного переноса электронов.

4. Реакция 2 протекает по механизму двойного замещения ("пинг-понг") и, в сравнении с реакцией 1, характеризуется на порядок более высокой скоростью и на порядок более низким сродством к окисленому нуклеотиду. Реакция не чувствительна к Ацн+.

5. В обеих реакциях NAD+ конкурирует с APAD+ и не конкурирует с NADH.

6. ADP-рибоза и реин по разному ингибируют две реакции, катализируемые нативным ферментом.

7. Заключено, что в реакции 2 функционирует отдельный нуклеотид-связывающий центр(ы), отличный от двух субстрат связывающих центров участвующих в реакции 1. Таким образом, в составе

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