Leucine (LEU), Valine (VAL), Isoleucine (ILE) and Histidine (HIS) Metabolism

00:01 The three amino acids leucine, valine and isoleucine are the next ones I want to consider.

00:07 Notice the branched-chain amino acids, the BCAAs, and they have some common features among them in their metabolism and some unique features as well.

00:16 We start with them in their decarboxylation by the attachment of a two-carbon piece to a molecule known as thiamine pyrophosphate.

00:24 Now valine and leucine pathways involve attachment of this two-carbon piece to pyruvate.

00:30 They have that in common.

00:33 The isoleucine pathway, by contrast, involves the attaching of this two-carbon piece to a molecule of aplah-ketobutyrate.

00:40 The penultimate products that is the precursors of these amino acids then become the following molecules.

00:46 Alpha-ketoisocaproate is a precursor of leucine by a transamination reaction.

00:51 Alpha-ketoisovalerate is a precursor of valine, again, by a transamination.

00:56 And finally, alpha-keto-beta-methylvalerate is a precursor of isoleucine, a third transamination.

01:04 Now, the synthesis of these amino acids is important to balance.

01:08 One of the themes that we've seen in metabolic pathways is the importance of making the right amount, not too much, not too little, of any given molecule.

01:17 And this is illustrated in the slide that I want to show here for these three amino acids.

01:21 Now, the synthesis of these three amino acids actually interacts with the synthesis of the breakdown pathway for threonine.

01:30 Threonine's breakdown involves the enzyme threonine deaminase.

01:35 We can see that illustrated at the top left of the screen.

01:39 The breakdown of threonine produces the molecule alpha-ketobutyrate.

01:43 And if you recall from what I said earlier, alpha-ketobutyrate is the precursor of isoleucine that involves the transfer of a two-carbon piece from thiamine pyrophosphate.

01:55 It's that transfer that produces the precursor that ultimately makes isoleucine and that's shown in the sort of central part of the screen.

02:03 We remember that there is also a transfer of a two-carbon piece from thiamine pyrophosphate onto pyruvate to make its precursors for valine and leucine.

02:14 So what we see is that this two-carbon piece attached to thiamine pyrophosphate is common to all three amino acids even though they go in different directions.

02:24 Well, this, the way in which these pathways interact with the threonine deaminase pathway is as we see on the screen here.

02:32 The starting material for isoleucine requires the production of threonine -- the action of threonine deaminase.

02:39 And the starting material for valine and leucine is pyruvate which comes from the glycolysis pathway.

02:45 There's the common molecule of all three.

02:47 So how does the cell balance these things? The cell balances it by controlling the activity of threonine deaminase, the precursor of isoleucine -- that makes the precursor of isoleucine.

03:02 High levels of isoleucine will inhibit the enzyme.

03:06 Now, this is known as a feedback inhibition.

03:08 Feedback inhibition occurs when a molecule at the end of a metabolic pathway inhibits an enzyme earlier in the pathway.

03:15 If the cell has too much isoleucine, it does not want to continue to make the precursor alpha-ketobutyrate, so it turns off the enzyme.

03:24 Well, if it turns off the enzyme, that means that this balance that's shown between alpha-ketobutyrate and pyruvate shifts in the favor of pyruvate.

03:33 Now, pyruvate will get preferential access to that two-carbon piece attached to the thiamine pyrophosphate.

03:39 That will favor the production of valine and leucine whenever isoleucine is high.

03:46 On the other hand, when valine is high, this will turn on the threonine deaminase and shift the balance away from pyruvate but back to alpha-ketobutyrate which now gets preferential access to the two-carbon piece to make the precursor to make isoleucine.

04:03 It's a nice balance, too much of one, favors the alternate pathway.

04:10 Now, the breakdown of the branched-chain amino acids occurs through a pathway known as the branched-chain alpha-keto acid dehydrogenase complex.

04:19 That's a mouthful of a name.

04:21 We see the generalized reaction by which this occurs at the very top.

04:25 We see the alpha-keto acid that shown on the left schematically.

04:31 And we an R group in the lower left part of that molecule.

04:33 That R group is a variable portion of the molecule.

04:36 And the different things that can be attached as that R group are shown for isoleucine, leucine or valine, so any of those can function as the R group there.

04:45 In this reaction catalyzed by this enzyme, the alpha-keto acid is being decarboxylated to form the molecules that are shown on the right.

04:54 There is the decarboxylation.

04:56 And if this enzyme is defective or deficient, then what will happen is a person who develops what's known as mapla syrup urine disease, they're unable to break down that precursor that's seen there, and their urine will look and smell like maple syrup.

05:11 Histidine is the last family of amino acids I want to describe here.

05:14 And it's a family that's all to itself.

05:16 There's no other amino acid in this family, so histidine stands unique among all of the amino acids.

05:22 Its synthesis is the most complex.

05:25 Histidine synthesis overlaps with nucleotide metabolism in involving ribulose-5-phosphate and also involving phosphoribosyl pyrophosphate or PRPP.

05:35 Now, there are 10 complicated steps that lead to histidine, and I'm not going to go through and describe each one.

05:42 The second enzyme of the pathway, which is known as ATP phosphoribosyltransferase is feedback inhibited by the end product of the enzyme histidine.

05:50 So histidine as it accumulates will turn off its own synthesis.