Biochemistry of Bilirubin

00:01 The topic of this set of lectures is that of the metabolism of bilirubin.

00:05 Bilirubin of course is a breakdown product of heme and heme is one of the components of our red blood cells.

00:13 Catabolism of heme actually begins in the spleen because it's in the spleen where the red blood cells are taken out of the blood supply.

00:20 In this process, damaged blood cells are recognized by the spleen and these damaged blood cells have contents that have to be processed.

00:27 One of the more important components of those blood cells, of course, is heme.

00:32 Heme is shown in the structure in the lower left.

00:35 Now the reduction of heme is the very first step in the process of converting heme into what will ultimately become bilirubin.

00:43 The first step in the process involves the production of biliverdin as you can see here.

00:47 And this reduction reaction uses electrons from NADPH.

00:51 It also uses oxygen.

00:53 And this oxygen is actually oxidizing a part of heme.

00:57 So this is a complicated reduction oxidation that's actually happening to make biliverdin.

01:02 Well the reaction is complicated, but the product is not very complicated.

01:05 As you can see, biliverdin looks very much like heme does on the left with the exception of the top bond that has been broken where two oxygens have been substituted.

01:15 Heme is converted in this reaction by the enzyme known as heme oxygenase that makes this overall process happen.

01:21 And again, we see the involvement of molecular oxygen as we have seen in numerous other metabolic processes.

01:27 There's the top bond that's been broken and there's the production of the two oxygen atoms that I described earlier.

01:34 Now the increased activity of heme oxygenase is important because it's a signal to the body to start making more ferritin.

01:42 What is ferritin? Ferritin is a protein that grabs and stores iron.

01:49 Iron in the body is something that the body has to be very careful of allowing in the free form.

01:55 This ferrous iron that we see here, Fe+2 or ++ as it shown here.

02:01 This ferrous iron can participate in reactions and cause some very serious byproducts that the cell of the body doesn't want to have.

02:10 So being able to contain this within ferritin is important.

02:13 So increased activity of heme oxygenase correlates with the production of ferritin.

02:18 And the reaction we've just seen, there was a reduction at the center joint that broke the conjugation and allow for flexibility in the molecule.

02:25 And the reaction we'll see here, biliverdin is converted into bilirubin.

02:29 And this involves breaking the bond of the very bottom of the molecule to allow the production of two of the molecules that you see here.

02:36 In the reaction, NADPH is used as a source of electrons to reduce the biliverdin into the bilirubin.

02:42 We see this bond that's here, that has been reduced in the process.

02:45 And the reduction of this bond changes the double bond, which is shown on the left, to the single bond, which is shown on the right.

02:51 Again, increasing the flexibility of this molecule.

02:55 This reaction is catalyzed by an interesting enzyme known as biliverdin reductase.

03:02 Now the formation of bilirubin is part of the reactive oxygen species reduction cycle.

03:08 Now this reactive oxygen species reduction cycle turns out to be really interesting component of bilirubin metabolism.

03:16 We'll see how this happens in just a second.

03:18 But this recycling system allows bilirubin to overcome a 10,000 fold excess of reactive oxygen species.

03:26 Now I'm going to remind you that reactive oxygen species, of course, are molecules that have free radicals involving oxygen.

03:34 These free radicals cause enormous problems in cells.

03:37 They can cause mutations.

03:38 They can cause formation of a lot of products that the cell doesn't want.

03:41 And this all happen in the absence of an enzyme.

03:44 So cells have a lot of things that they use to control the amount of reactive oxygen species produced, and this bilirubin as seen here is an important component of it.

03:55 So, so far what you've seen is that heme is converted to biliverdin by heme oxygenase, and biliverdin is converted to bilirubin by biliverdin reductase.

04:04 Bilirubin can be further process and excreted which I'll talk about later in this lecture.

04:09 Or alternatively, bilirubin can be oxidized back to biliverdin.

04:16 And this oxidation actually maps up reactive oxygen species.

04:20 And we can see that there's sort of a circle that's here.

04:24 You may remember from an earlier lecture in this series that there was a circle involved in the production of peroxide chain reaction.

04:33 This was actually causing peroxides to form in metabolism, I shouldn’t say metabolism, but in the oxidation of fatty acids that was very undesirable.

04:42 That cycle kept throwing out additional peroxides that cause problems.

04:47 Here is a cycle that is containing the reactive oxygen species.

04:52 Now this cycle counteracts other cycles that cause problems.

04:55 So this cycle is very important for cells to help manage reactive oxygen species.