/war flashbacks to ochem
except there's no arrow pushing or retroactive synthesis problems so I think I got this

DRUG METABOLISM!! staring with phase 1 reactions, in which we're adding/modifying functional groups so they can be masked in phase II for excretion. A large majority of metabolism is done by monooxygenases, the main enzyme being cytochrome P450 (NADPH, H+, O2) so when in doubt, guess cyp

Let's begin with some general oxidation reactions catalyzed by CYP-- it catalyzes a lot of things, but I bundled these up into one structure because they're all pretty simple transformations from R-H --> R-OH. When looking at drug structures, key things to look out for are phenyl rings, alkanes, and alkenes. Basically almost every carbon, idk. Phenyl and alkenes for sure though, because they form epoxides which are very reactive due to the strained 3 member ring, not good things to have in your body.


For amides/amines, the degree of substitution determines whether the reaction is catalyzed by CYP or FMO, both of which are monooxygenases. CYP uses a heme group to deliver the reactive oxygen that's donated to the molecule though, so it's better with less substituted amines. Other than that, just follow the structure and add an oxygen to the nitrogens. CYP reactions tend to look like (R-H --> R-OH) while FMO is (R-H --> R-O), so that's how you can remember the funky tertiary amine product.


FMO's (R-H --> R-O) is more evident in sulfoxidation where there's a two step process replacing the hydrogens with oxygen. The sulfoxide is the major product, but the final end product is a sulfone, and its structure is easy to remember since sulfur has six valence electrons and will want to make six bonds.


That's the end of oxidation reactions! Now it's more complicated things that just simply swapping out H's for O's.

From the above oxidation reactions, you see a lot of hydroxyl groups formed, so first we'll tackle metabolism of those alcohols. Alcohols are dehydrogenated by alcohol dehydrogenase! They form aldehydes, which are dehydrogenated by aldehyde dehydrogenase!! The enzyme names for these two are super simple to remember; what's going to trip me up are the reversible arrows for ADH (forward rxn occurs when the ratio of NAD+:NADH is high; reverse when the ratio is low). I'll try to think of it as alcoholism, where it's easy to relapse and go back to an alcohol after you've gotten out. ALDH also uses NAD+, and also water to donate that extra oxygen. So as long as I remember it's NAD+ for the cofactor, I'm set.
SO LONG AS I REMEMBER. Because look at the next reaction with DHDH, the cofactor is NADP+ and now I'm juggling around all these different cofactors (NAD+, NADH, NADP+, NADPH, when will it end; apparently the cell uses the +/H to determine forward/reverse, and the P to differentiate targets, but still ahhhhhhh). At least it's specific to dihydrodiol, there's no way I'll miss two -OHs. Two step process to a quinone, which is a pain to get rid of, quinones are terrible.


With that taken care of, CYP can go on to metabolize all sorts of other stuff. De-something-ation reactions remove that something and replace them with oxygen, just like CYP replaces H with O in those earlier examples. Except sometimes, in adding that O in, you get unstable intermediates that kick out a functional group. Alkyl groups and halides are pretty easy to kick off, so they're cleaved from the rest of the molecule. Sulfur too, even though I didn't draw the arrow pushing, it goes on its happy way with oxygen filling in for it.


DEAMINATION THOUGH ISN'T CATALYZED BY CYP!! MAO takes up this task instead, specifically for primary amines and it has all these messy side products. MAO --> cat --> super high maintenance like they're head of house (1 amine) and bitey teeth and sharp claws are dangerous (ammonia, hydrogen peroxide, note the D: face)


Beta-oxidation is also another weird one where you're upping the number of carboxylic acids, I don't know how much that helps the molecule but I guess it does. It's weird, and involves many enzymes so I'm not going to worry about this one.


Now we're on the flipside of oxidation, which is reduction. CYP is involved with almost all of these as well, with the exception of carbonyl reductase, but both enzymes use NADPH as their cofactor, thank you for making this easy for me. With reduction, I like to think of it as reducing the number of bonds, so all those double bonds are going poof. Carbonyl =O becomes plain -OH; the azo -N=N- become two -NH; and the nitro -NO2 has a double bond too that's removed through several unshown steps (so many steps. so many that even the oxygens are removed)
AND THEN THE QUINONE that I said was bad news. It can reduce to a nice safe hydroquinone, but CYP catalyzes an incomplete reduction into a radical, which can react with oxygen to create even more radicals and then you have DNA/RNA/protein/tissue damage and it's just ))):


So we've got all this mess floating around now that we've modified and chopped off the drug molecule. Next time, we'll go over Phase II conjugation reactions, stick a goodbye tag on these molecules and kick them out!!