My one story house has the air handler in a closet (with the hot water heater) in the center of the house.   The closet interior has has no trim (baseboards) and has sheetrock but doesn’t have taped seems, etc.  There are two doors to the closet.  The air handler goes up to the attic and the sheetrock around it has decent gaps on one side.  There are two large vent pipes going from the closet up to the attic.

So it seems my best option to focus on sealing between the closet and the interior of the house?  Due to the two large vent pipes, any sealing between the closet and attic seems pretty much useless.  

Any tips or suggestions on best approaches on this is greatly appreciated!