Ok that was a serious oversight on my end, my apologies. I forgot to mention this crucial bit of information in the main post.
When I open a new window, the *Edit > Substitutions > Smart Quotes` menu does remain enabled and work as expected if I’m editing, say, a Markdown document. When I said in the main post that this menu becomes disabled, it seems to only apply to the various text boxes in the UI, e.g., Name/Aliases/URL and so on in the Generic inspector, or if you click on a database/group/record to rename it.