MELBOURNE, Australia (AP) — It wasn’t just Serena Williams’ serve that was missing Monday at the Australian Open. It was her aura, too.

Ekaterina Makarova, the lowest-ranked player left in the draw at No. 56, didn’t seem the least bit frightened of the error-ridden opponent across the net.

The Russian won 6-2, 6-3 — equaling the biggest Grand Slam defeat of Williams’ 17-year career — and will face Maria Sharapova in her first Grand Slam quarterfinal.

Sharapova rallied past Sabine Lisicki 3-6, 6-2, 6-3 before men’s defending champion Novak Djokovic fended off a resurgent Lleyton Hewitt in a dramatic last match of the day, winning 6-1, 6-3, 4-6, 6-3.

With Hewitt’s loss, Australia’s chances of celebrating a home singles winner were over. American hopes had already evaporated with the defeat of five-time champion Williams — her first in Melbourne since 2008 and earliest since 2006.

“I can’t even describe how I served, to be honest,” said Williams, who finished with seven double-faults and a first-serve percentage of just over 50. “My lefty serve is actually better than that. Maybe I should have started serving lefty.”

Williams also threw in 37 unforced errors, but Makarova played her part, boldly going for the lines and holding steady in a tight service game while leading 4-3 in the second set. Playing Williams in Beijing in 2009, Makarova said she had been “afraid” of the American in a 6-3, 6-2 loss.

Not this time.

“I really thought that I could beat her,” Makarova said. “Maybe in my head that helped me.”

Williams tried not to blame her left ankle injury from a tuneup tournament in Brisbane two weeks ago. But she didn’t move well and seemed to have particular difficulty running to her left. She said if it hadn’t been a Grand Slam, she wouldn’t have played at all.

“Usually I play myself into the tournament,” Williams said. “But I don’t have a huge problem with an injury. So this is a completely different situation. Usually it’s easier for me to play myself in because I’m usually physically OK.”

At 30, Williams’ body is breaking down more often and, unlike earlier in her career, a lack of matches leaves her susceptible to upsets.

After squandering the fifth game of the second set with four double-faults, Williams threw up her arms in disbelief and yelled, “Oh, my God.” Her mother, Oracene Price, who doesn’t usually betray any emotion, shook her head in the stands.

Williams got away with a shanked smash in her third-round win. On Monday, she sent an overhead way beyond the baseline when a winner would have given her two break-back points in the second set.

“Every ball that came, I just hit it as far out as I could,” Williams said.

Before the match, 18-time Grand Slam champion Martina Navratilova said Williams was the best player in the world — “just a matter of whether she can bring it.”

Williams couldn’t bring it against Makarova, nor against Sam Stosur in the U.S. Open final in September, when she also only won five games. The only other time she has lost by so much in a Grand Slam match was against Sharapova in the 2004 Wimbledon final.

Williams will now return to the practice court in preparation for the United States’ Fed Cup match against Belarus on Feb. 4-5.

Sharapova can look forward to a quarterfinal against Makarova after overcoming her own problems in her fourth-round match. Sharapova hit eight double-faults and made 47 unforced errors but, unlike Williams, found a way to win against the 14th-seeded Lisicki.

“I fought to the end and sometimes that’s what gets you through,” said the Russian, who lost six games in a row after taking a 3-0 lead in the first set.

Djokovic had won 23 straight sets at Melbourne Park before he suddenly wobbled against Hewitt, a two-time Grand Slam champion who has slipped to No. 181 in the rankings after a series of injuries.

Hewitt, a wild-card entry in his 16th straight Australian Open, rallied from 3-0 down in the third set in front of a raucous home crowd to force a fourth set, but Djokovic gathered his composure.

“I think for two sets and 3-0 I was playing really well and suddenly I stopped moving,” Djokovic said. “He was not making a lot of unforced errors. I made a lot of unforced errors in the third set.”

Next up for Djokovic is fifth-seeded David Ferrer of Spain, who had a surprisingly easy 6-4, 6-4, 6-1 win over Richard Gasquet.

No. 2 Rafael Nadal and No. 3 Roger Federer are back in action Tuesday, hoping to set up a semifinal. Federer plays former U.S. Open champion Juan Martin del Potro while Nadal faces Tomas Berdych.

On the women’s side, defending champion Kim Clijsters will test her injured ankle against top-seeded Caroline Wozniacki, and third-seeded Victoria Azarenka plays eighth-seeded Agnieszka Radwanska.

Wimbledon champion Petra Kvitova opened Monday’s play with a 6-2, 7-6 (2) win over former top-ranked Ana Ivanovic. She’ll next play Sara Errani of Italy, who beat 2010 semifinalist Zheng Jie 6-2, 6-1.

Two-time finalist Andy Murray advanced when Mikhail Kukushkin of Kazakhstan retired after 49 minutes with a left hip injury while trailing 6-1, 6-1, 1-0. After knocking out the first player from Kazakhstan to reach the fourth round of a Grand Slam, Murray’s next opponent will be another history-maker.

Kei Nishikori beat sixth-seeded Jo-Wilfried Tsonga 2-6, 6-2, 6-1, 3-6, 6-3 to become the first Japanese man to reach the quarterfinals of the Australian Open since the Open era began in 1968.