ALAMEDA — If Derek Carr and Peyton Manning are on edge this week, it is with good reason.

Headed Carr’s way Sunday will be Denver outside linebackers DeMarcus Ware and Von Miller, who have combined for a league-high 49 quarterback pressures according to the Pro Football Focus website.

Manning, to whom mobility is a foreign concept at age 39, will avert his defensive gaze to spy Raiders defensive ends Khalil Mack and Aldon Smith — a duo that has been together for only a month but over the past two weeks is showing signs of similar malevolence.

“I hadn’t looked at it like that, but you’re right, there are great matchups on both ends,” Raiders left tackle Donald Penn said. “Our offensive line has its work cut out for us, but so does theirs.”

Denver (4-0) leads the NFL with 18 sacks, with Ware’s 4.5 the most in the league. The Raiders (2-2) have eight sacks but are heating up. Mack’s three sacks have come in the past two games, and Smith, signed as an unrestricted free agent before the start of the regular season, got his first sack last week and has accumulated 18 pressures.

Smith, who had 42 sacks in 43 games over his first three seasons with the 49ers and is looking to get back into top form after a series of personal issues, admits being energized by the pass rush talent on the field.

“Just the competitive nature of us, we all want to compete and prove who is the best out of all of us,” Smith said. “We’ll all be out there trying to make our mark.”

Denver, which switched from a 4-3 alignment under former defensive coordinator Jack Del Rio to the 3-4 favored by veteran defensive coordinator Wade Phillips, already has sacks from 11 players — with the focus on Ware and Miller opening things up for others.

Del Rio maintains there isn’t much difference in dealing with Ware and Miller than there was when he was in charge of the Denver defense under John Fox. Ware was listed as an end in the 4-3 defense and welcomed the switch to a 3-4, which he played under Phillips at Dallas.

“The biggest change for a guy like DeMarcus is he will spend less time wrestling with tackles on run downs and more time on backs and tight ends,” Del Rio said. “Other than that, they are basically in similar spots.”

Ware, 34, is just one sack behind Lawrence Taylor for 11th place all-time since sacks were first kept as a statistic in 1982. Miller registered 50 sacks in his first 58 games and has had double-digit sacks in three of his first four seasons.

In the past month, Mack has watched Smith closely. The two had never met until Smith set foot in the Raiders locker room, and Mack found his new teammate to be a “funny cat” and willing to share his secrets.

In particular, Mack has watched Smith’s “stab and swipe,” a move where he jolts an offensive lineman in the chest and follows with a swipe to the arm between the forearm and elbow to gain an instant advantage.

“It’s all about wreaking havoc on the edges,” Mack said.

Safety TJ Carrie (chest), defensive tackle Justin Ellis (ankle), defensive end Denico Autry (concussion) and special teams player and running back Taiwan Jones (foot) were all ruled out and will not face Denver. Larry Asante will take Carrie’s spot in the secondary. Ellis, who played last week, re-injured his ankle in practice during the week. With Carrie and Jones out, Del Rio wasn’t ready to go public with his plans on returning punts and kickoffs.