Divine Intervention Episode 50 Comprehensive Step 1 ..., Study notes of Biochemistry

Download Divine Intervention Episode 50 Comprehensive Step 1 ... and more Study notes Biochemistry in PDF only on Docsity!

Divine Intervention Episode 50

Comprehensive Step 1

Biochemistry Review (Session 1)

Some PGY

Introduction

-Primary goal is to review metabolism as relevant to Step 1.

-My approach today will be to use a combo of questions AND

mechanistic explanations of stuff to make you feel very comfortable

with Step 1 metabolism.

-Where appropriate, I’ll integrate Pharm, Pathology, and Physiology.

-I am going to spend a lot of time going over how the material WILL

be tested.

Pyrimidine and Purine Synthesis (+ The 2 Orotic Acidurias)

Pyrimidine and Purine Synthesis (+ The 2 Orotic Acidurias)

Protein Digestion

-Starts with the low pH environment of the stomach (denaturing) and the action of pepsin from chief cells.

-Pancreas releases trypsin, chymotrypsin, carboxypeptidase, etc (to digest protein). The initial kickstarter for this process is enterokinase (working on trypsinogen).

-AAs are reabsorbed in single AAs (and also as di/tripeptides, vs glucose). This requires Na symport.

-HY disorders to know here include Hartnup disease (gut + renal neutral AA transport like tryptophan) AND Cystinuria (gut + renal basic AA transport like cysteine, can cause renal stones with a specific shape?? And can be treated with a drug??)

Dealing With Our Protein Problem

-We love protein as humans. However, they have a problem that we have to deal with on a daily basis (ammonia). We deal with this problem through the urea cycle and partially with ammonium excretion.

-To make your life easy, think of the body having only 2 NH3 carriers (glutamine and alanine). The only source of alanine is muscle (why does this make sense?).

-The kidney has an enzyme (glutaminase) to strip the NH3 off glutamine, add a H+, and then excrete the NH3 as NH4+.

-The liver primarily forms urea (which can travel safely in the blood w/o trouble). Urea has 2 amino groups. These 2 amino groups come from 2 sources-> glutamate and aspartate.

-If you understand these basics, the urea cycle becomes very doable. Go over it again!

The Urea Cycle Key Takeaways

-There are only 2 enzymes you need to know in the urea cycle-CPS 1 and Ornithine Transcarbamylase.

-Location matters here. First 2 steps are in the mitochondria. Final steps are in the cytosol. These “double location” details are HY for Step 1!

-Primary regulation here is with N-Acetylglutamate being an obligate CPS1 activator (makes sense, NAG is something you’d potentially get from a “high protein meal”, taking in proteins should logically make you upregulate the pathway that deals with ammonia problems).

-NH2 group #1 comes from Step 1. NH2 group #2 comes from Step 3 (aspartate).

-Don’t forget your pesky arginine details (histones, NO synthesis). How would you manage hepatic encephalopathy??

The Urea Cycle

Protein Breakdown Diseases (super HY!) + VOMIT pathway

-Remember your PKU and a mousy/musty odor (and PAH or THB reductase deficiency). Tyrosine becomes an essential AA.

-Albinism is associated with a tyrosinase deficiency (tyrosine to melanin).

-Alkaptonuria is associated with a homogentisic acid oxidase deficiency. Homogentisate makes urine blue black and causes joint disease (from deposition).

-Branched chain ketoacid DH breaks down branched chain AAs (LIV). A deficiency in this enzyme causes MSUD. This enzyme is also HY from the standpoint of some eerie relationship to the PDH complex and alpha ketoglutarate DH.

-Homocystinuria (SH groups) can be caused by a CBS (B6) deficiency or a homocysteine methyltransferase (methionine synthase, B12) deficiency. What are 2 key details that differentiate this disorder from Marfan’s (think IQ and eye findings)?

Protein Breakdown Disease Summary

Vitamins and Minerals -Learn your vitamins and minerals in the context of folate metabolism and phenylalanine metabolism (contain most of the vitamin info you need for Step 1).

-For phenylalanine metabolism, remember our stories with PKU, Albinism, Parkinson’s treatment, Vitamin C (and its role in collagen synthesis), PNMT and its special role in the adrenal medulla, and the HVA/VMA role in diagnosing a pheochromocytoma.

-There are 2 KINDS of folate in the body -> active folate (AF, with a charged C) and storage folate (SF, with a methyl which is largely unreactive). All the fancy stuff folate does in the body is with its AF form. SF seems to be largely useless until you recognize one key fact -> It is a precursor to AF (with this irreversible interconversion carried out by homocysteine methyltransferase/methionine synthase, requires B12).

-Folate is needed for pyrimidine synthesis (remember thymidylate synthase?). W/o DNA from folate, cells increase in size w/o “nuclear doubling” -> megaloblastic anemia.

Tyrosine Metabolism and Parkinson’s Disease and PNMT

Another Step 1 Worthy Question (+ B12 depleting bug)

B6 (Pyridoxal phosphate), B9 (Folate), and B

(Cyanocobalamin) deficiencies can all cause

homocystinuria. How would you differentiate b/w a

B6 vs B9/12 deficiency as a cause of homocystinuria

(think of the other elevated stuff)? After doing this,

how would you differentiate b/w B9 and B

deficiency as a cause of homocystinuria? What are

the 2 classic NBME folate deficient patients?

The Heme Synthesis Pathway (+ avoiding barbiturates) -You need to know 5 enzymes in this pathway and some associated stories.

-ALAS is the rate limiting enzyme (B6 cofactor, re-Isoniazid). It is inhibited by heme.

-Pb poisoning (moonshine, old house) can cause a sideroblastic anemia with an increase in free erythrocyte protoporphyrin from ALAD and Ferrochelatase inhibition. Note your classic blood smear findings (+ neuro, + wrist drop, + abdominal pain).

-A porphobilinogen deaminase deficiency is associated with AIP (no photosensitivity but neuro problems, port wine stained urine). So happens that Uroporphyrinogen 3 is the first porphyrin in this pathway and since it comes after PBGD, we don’t have a “photoactive” substance building up.

-A UROD deficiency is associated with Porphyria Cutanea Tarda which does have photosensitivity (+ hirsutism, + Hep C association, + intense “hand” sweating).