Metal Containing Enzymes

00:00 Now, I’d like to bring you on to metal containing enzymes. Metal-activated enzymes associate loosely with ions. And they usually come from the group 1 or group 2 part of the periodic table.

00:14 Although some of them, as we will see, such as zinc or iron containing enzymes come from the transition metal. And they use these ions to adopt a specific structure or shapes, sometimes bringing together more than one protein.

00:30 Metalloenzymes is the general name for these and they contain tightly bound metals usually from the transition block which can bind substrates in specific orientations and carry out RedOx reactions with changes in the metal oxidation state. It’s also possible for them to stabilise negative charges. Around a third of all enzymes require the presence of a metal ion for activity.

00:59 So, let’s have a particular look at our friend carbonic anhydrase. This is the enzyme, if you remember, that’s is responsible for the conversion of carbon dioxide and water into hydrogen carbonate.

01:13 Here, you can see a diagram which shows the orientation of different amino acid residues in relation to zinc, which remember is found as a transition metal within the periodic table, in order to hold these particular groups together.

01:30 Note the coordination of the histidine 96 residue, the histidine 94 residue and the histidine 119 residue. So, all of those key histidine residues are donating electrons into the shell of the zinc ion in the center.

01:48 Also, note the coordination with water that's shown here as H2O. This is very important in relation to how it coordinates with the carbon dioxide. So, how does it actually work? Let’s go through it step by step.

02:03 Here we have, in the left hand side corner, a zinc which is tetrahedrally coordinated to the imidazole rings of 3 histidine residues and if you are unsure as to what we mean by that, I recommend that you look up histidine as an amino acid.

02:19 And you will see that you are looking at the imidazole nitrogen containing cyclic structure which donates electrons into the zinc positively charged cation and holds it together.

02:32 In the first instance, what we have is water coordinated to the Zn2+, the zinc ion, as we saw in the previous diagram. What happens in this scenario is the coordination makes the one of the protons on the water more labile and this results in the coordination effectively of a hydroxyl group to the zinc 2+ resulting in the loss of H+, as we can see.

02:56 Now, we have a negative charge on that oxygen, this can then nucleophilically attack our carbon dioxide, shown here on the right hand side. Bear in mind, if you recall back when we were talking about dipoles, it’s important to realise that where we have those two very electronegative oxygens pulling electron density away from that carbon, that carbon itself is going to be quite delta positive.

03:22 This means the negative charge on the oxygen would find it easy to carry out a nucleophilic attack on that carbon breaking open that carbon oxygen double bond.

03:32 Once that happens, you have a coordination effect, as you can see here, where you have the oxygen, now covalently bound to the carbon of the carbon dioxide. And this ultimately results in the release of hydrogen carbonate.

03:47 Note now, the complex iron CO3- is only loosely bound by that dative covalent bond shown as a dash between the zinc 2+ and the oxygen and HCO3 can be produced.

04:05 Enzymes and drugs.

04:06 So, not only are enzymes important in maintaining reactions within the body, everything from, as I said, glycolysis, metabolism, catabolism and so forth, they are also important in regulating drug action.

04:21 Enzymes bring about drug metabolism and of particular importance are the cyctochrome P-450 mixed function oxidases that are often found in the liver.

04:32 Some enzymes can be used to activate pro-drugs, as we have already said and as we will see in greater detail a little later on. Enzymes themselves can sometimes be drug targets.

04:42 And some disease states arise through the malfunctioning of a specific enzyme.

04:48 If the body is, for example, attacked by foreign invaders, e.g. micro-organisms or viruses then these can be halted by the interference with their enzymes.