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Let’s face it, the urea cycle is dry and annoying as fuck, but you don’t have to memorize it like this is undergraduate biochemistry.
I was in Pittsburgh for New Years 2011-2012, just before I started studying for my own Step 1. I was at a pizza place, and there were two guys in line with me talking about medicine. As it turns out, they were residents in radiology and surgery and had aced their Steps. Call it dumb and dorky all you want, but I started asking them about how to prepare for the Step.
Correct, of all times to talk about USMLE, I did it on New Years.
One of the guys, super-drunk and with eyes wide-open, said to me:
“Arginase……..Know arginase……..It’s the last enzyme in the urea cycle. It’s the actual one that makes urea.”
I was like, “Okay, got it. I’ll make sure to remember that.”
And he goes, “No…you don’t understand…that was on my exam. They asked ARGINASE. You need to know ARGINASE.”
I remember leaving the pizza place thinking it was like the movie The Matrix, as though I had met the Oracle who intervened and told me what was going to be on my exam. I remembered that detail the whole next year, convinced it would show up on my Step. It never did. But I’ve always made sure to tell my students that detail either way.
I’ll say, “Look, it’s dumb I know. The urea cycle is dry and boring as fuck. But just know arginase. It’s apparently asked.”
And one of my students once got back to me after the exam and said it showed up. They were like wow wtf thank you.
So as I said, know arginase. Hopefully that mini-story makes it stick.
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The USMLE also has some sort of magical obsession with N-acetylglutamate.
| Yes, for some undisclosed magical reason, the USMLE is infatuated with N-acetylglutamate. Just know it’s a positive allosteric regulator of CPS-I. I promise you this shows up. |
In questions, they’ll tell you that a patient has hyperammonemia, there is increased ornithine, and that urea cycle enzyme levels are normal. The answer is N-acetylglutamate deficiency.
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The USMLE also really wants you to know that ornithine transcarbamylase (OTC) deficiency is X-linked recessive. I do not know why, but that is high-yield in urea cycle questions.
They also want you to be able to contrast between OTC and orotic aciduria.
Orotic aciduria is a condition of impaired pyrimidine biosynthesis, where orotic acid is an important precursor molecule that cannot be converted to downstream intermediates. It is caused by deficiency of the enzymes OPRT and ODC (you won’t get asked these).
In both OTC deficiency and orotic aciduria, increased serum orotic acid is seen, however there are some key differences:
In OTC deficiency, because the urea cycle is impaired, blood urea nitrogen (BUN) is lower. There is, however, a buildup of ammonia because of the failure to convert it to urea (BUN). In addition, there is no impairment in pyrimidine synthesis, so MCV is normal.
In orotic aciduria, the urea cycle is intact, so serum ammonia and BUN are normal. However MCV is increased because pyrimidine synthesis is impaired.
| Patient has ↑ serum orotic acid:
Normal MCV, hyperammonemia, ↓ BUN → OTC deficiency (X-linked) ↑ MCV, normal ammonia + BUN → Orotic aciduria (AR) |
In orotic aciduria, there’s an actual impairment of pyrimidine synthesis, so there’s slowed bone marrow production of nucleated erythrocyte precursors.
But in OTC deficiency, there’s merely a shunting of carbamoyl phosphate toward the pyrimidine biosynthesis pathway (where orotic acid is produced), so the latter is incidentally increased, but there’s no impaired pyrimidine synthesis.
That’s it. Yes, we could sit here and talk about # of ATP used, etc., + what occurs in the cytosol vs mitochondria, but the point is to get you a high score on the USMLE, not to give you an unabridged, boring as fuck college biochemistry lecture.
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