Ukraine club Shakhtar, winners of the final edition of the UEFA Cup last season before the competition was re-branded, were gifted the lead with a Marko Lomic own goal before cruising to victory with Luiz Adriano, Jadson and Yaroslav Rakitskiy all on the scoresheet as they moved to six points from two games.
Shakhtar also won their opening match 4-1 against Club Bruges.
PSV Eindhoven replaced CFR Cluj at the top of Group K after beating the Romanians 1-0 with Otman Bakkal's early header but fellow Dutch heavyweights Ajax Amsterdam had to settle for 1-1 draw away at Anderlecht in Group A.
Valencia, one of three Spanish clubs in action on a night of 24 ties, beat Italians Genoa 3-2 in Group B but Villarreal lost 2-0 to Salzburg in Group G as the Austrians followed up their opening victory over Lazio.
Serie A Lazio won 4-0 at Levski Sofia.
Werder Bremen beat Athletic Bilbao in Group L, Aaron Hunt's volley paving the way for 3-1 victory for the Bundesliga side who were beaten by Shakhtar in last season's UEFA Cup final.
Fans paid a minute's silence in memory of Brice Taton, the Toulouse fan who was beaten by Partizan fans on September 17 and died on Tuesday, as the French club drew 2-2 with Bruges.
