Proline and Arginine Synthesis

00:01 That next amino acid we consider in biosynthesis is that a proline.

00:06 Proline is made in a relatively simple fashion in three steps starting from glutamate.

00:11 The first step involves the synthesis of glutamate-5-semialdehyde which I don't show here.

00:17 The first step beyond that then is the phosphorylation of the glumate-5-semialdehyde.

00:23 That oxidation and dephosphorylation is necessary to produce the cyclization intermediate.

00:28 And that's what we see on the screen below.

00:31 The cyclization that happens of glutamate-5-semialdehyde is spontaneous and does not require an enzyme.

00:37 We can see that cyclization actually happening to make one pyrroline-5-carboxylic acid.

00:43 Cyclization happens without any other thing being present in the reaction.

00:47 The last step that one pyrroline-5-carboxylic acid gets reduced and the reduction of that produces the amino acid proline.

00:56 Arginine is an amino acid that can be made in multiple ways.

01:00 In arginine, as we will see in the urea cycle, is a very important sort of central enzyme for doing a variety of things.

01:07 So there four ways to make arginine and I'll describe them right here and then show you later how those reactions occur.

01:14 The first is a forward reaction that takes two steps coming from citrulline and ATP and aspartate.

01:20 That process occurs in the urea cycle in the normal direction of the urea cycle.

01:26 The second way of making arginine is production from asymmetric dimethyl arginine or ADMA.

01:32 This is a modified form of arginine that's found in proteins.

01:36 It differs from arginine in having a metal group and that metal group is put on to arginine after the protein is made.

01:43 To get ADMA, one has to break a protein down by using proteolysis and then ADMA is released.

01:50 So, ADMA is made into arginine after a protein has been broken down.

01:55 The third reaction for making arginine involves a reversal of a reaction of the urea cycle using the enzyme arginase.

02:03 This reaction involves the molecule known as ornithine and we'll see how that actually is produced.

02:09 The last way of making arginine is a reaction that involves nitric oxide.

02:13 This is reaction that is actually used to make nitric oxide in cells and it involves citrulline, nitric acid, and NADP.

02:20 So arginine is a central part of the urea cycle.

02:23 And remember that the function of the urea cycle is to produce urea for excretion because excess amines are problematic.

02:30 The cell has to be able to have arginine in order to do that.

02:34 The ADMA reaction that actually goes backwards to produce arginine interferes with the production of nitric oxide.

02:40 Nitric oxide is a very important signaling molecule that cells use.

02:45 So again, cells have to balance need for one molecule versus need for another in considering which pathway is used to make a molecule.

02:54 Arginine may play role in very important diseases involving cardiovascular disease, diabetes mellitus, erectile dysfunction and kidney disease.

03:02 So it's a very important amino acid.

03:05 Deficiency of the enzyme arginase is another important reaction to consider because it leads to the genetic disease known as argininemia.

03:15 And argininemia as we will see for other amino acids involves the accumulation of arginine and more importantly ammonium ions in the blood.

03:23 Thos ammonium ions as we can describe are toxic.

03:27 Well, in this set of slides, I want to show now the reactions that I've just described previously the four ways of making arginine.

03:36 We see arginine in the lower part of the screen and we see how it connects to these molecules that I've been describing.

03:42 We start with reaction number one which involved the production of arginine from citrulline reaction -- set of reactions that occurs in the urea cycle.

03:51 There are two steps as I've described.

03:53 The first step being a very energy-intensive step that involves the cleavage of ATP to make AMP plus two inorganic phosphate ions.

04:02 This reaction is central to making arginine in the urea cycle but it's a very energy-intensive reaction.

04:08 So cells again, are cautious in how much they use to do this.

04:12 In each of the reaction that I show here, the green arrows point in the direction of making arginine.

04:18 And we see that each reaction is reversible so there's an arrow pointing the other direction that can go on different circumstances.

04:26 Argininosuccinate which is a product of the first reaction is converted into arginine in the next step, and we can see that was the product of arginine for pathway number 1.

04:36 ADMA after approaching has been broken down can be demethylated to make arginine as we have seen.

04:42 And we also see that by starting with ornithine and urea and going upwards with the lost of water, we can make arginine.

04:50 Now, normally, this reaction as it occurs in the urea cycle involves the downward direction.

04:57 So, in order to make arginine, we have to actually reverse that reaction.

05:00 Normally, that's not a very common way of making arginine.

05:04 The last way of making arginine is also a reversal of a reaction that occurs in the cells and this involves the nitric acid signaling that I've described before.

05:12 If we make arginine using this pathway, we use nitric oxide.

05:18 And nitric oxide, as I said, is an important molecule for signaling.

05:21 So, cells are careful again in how much this reaction is moved to the right versus how much it's moved to the left.

05:28 This reaction is an oxidation and we can see the oxidation occurring as a result of the NAPD being converted into NAPDH.