South Africa, who made a mammoth 517 in their first innings, removed both Pakistan openers, Shan Masood and Khurram Manzoor, without scoring before lunch to further close in on a series-levelling win at Dubai stadium.
Pakistan also lost Azhar Ali (19) and were struggling at 56 for three at tea with Younis Khan (29) and skipper Misbah-ul Haq (seven) at the crease.
They need another 362 runs to avoid an innings defeat.
It became two for two when Manzoor fell for his second duck of the match, caught off a miscued drive off Vernon Philander from the fifth ball of the second over.
Also Read
Manzoor had made 146 in Pakistan's seven-wicket in last week's Abu Dhabi Test.
Azhar Ali and Younis added 46 for the third wicket before part-time spinner Jean-Paul Duminy struck with his first ball, trapping Ali lbw with a low delivery.
Pakistan were bowled out for a paltry 99.
In the morning session, South Africa lost their last six wickets for the addition of 57 runs after resuming at 460-4. Off-spinner Saeed Ajmal finished with 5-161 while paceman Mohammad Irfan took 3-102.