Week 12 Bioinorganic Chemistry Workbook - Monash S2 2024 PDF

10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 Week 12 - Bioinorganic chemistry - workbook Site: Monash Moodle1 Printed by: Kaltham Alzaab...

10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 Week 12 - Bioinorganic chemistry - workbook Site: Monash Moodle1 Printed by: Kaltham Alzaabi Unit: CHM1022 - Chemistry II - S2 2024 Date: Sunday, 13 October 2024, 8:05 PM Book: Week 12 - Bioinorganic chemistry - workbook https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 1/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 Table of contents 1. Pre-workshop material 1.1. Bioinorganic metals 1.2. Biological Molecules as Ligands 1.3. Activity 1 1.4. Oxygen carriers 1.5. Activity 2 1.6. Zinc 1.7. Metals in Medicine 1.8. Metals in Imaging and Diagnostics 2. Summary 3. Preparation quiz 4. Online lectures 5. Workshop https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 2/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 1. Pre-workshop material Biological inorganic chemistry Bioinorganic chemistry uses the principles of coordination chemistry to understand how biological pathways work and how these metal ions and ligands may interact with biological function, through coordination. Many functions of the human body require metals. Biology uses metals ion and ligands to form complexes that have a variety of biochemical properties. For example the alkali metals sodium and potassium help to regulate osmotic control and the actions of nerves, whereas the alkali earth metal magnesium is often found in metallo-enzymes and functions to help muscle movement. Calcium is found in your bones and teeth, playing an important part of structural chemistry. Other metals, including many from the first row of the d-block are found in trace amounts, but are still essential to homeostasis within the body. Figure 1 below shows the elements used by biology - green = widespread use; blue = elements that are trace/suspected to be used and orange = very rare use. Figure 1 Metals in the human body - adapted from Inorganic Chemistry, Oxford, 7th Edition https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 3/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 1.1. Bioinorganic metals Biological essential elements can be classified as either 'major' or 'trace', with levels varying considerably between different organisms. With respect to the first row of the transition metals, Fe and Zn are the most abundant. Below you’ll find a summary of the mass of each trace metal in a 70 kg human along with where these metals are found within the body and some of the biological roles they have. Metal Mass/mg Biological role V 0.11 Enzymes such as nitrogenases Cr 14 Glucose metabolism in certain animals Mn 12 Enzymes such as phosphatases, in plants redox activity (photosystem II) Fe 4200 Haemoglobin/myoglobin, iron storage (ferritin, transferrin) transport proteins etc Co 3 Vitamin B12 Co-enzyme Ni 15 Enzymes such as ureases Cu 72 Electron transfer systems, transport proteins Zn 2300 Enzymes such as alcohol dehydrogenase, carbonic anhydrase https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 4/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 1.2. Biological Molecules as Ligands Please read Section 24.1 Amino acids of Chemistry, Blackman et al. (4th ed.) Amino acids and proteins Amino acids (and the protein structures they generate) are a major source of ligands in biological systems. There are twenty-one amino acids as seen below in the table. While the carboxylic acid and amine group on the α-carbon do not form a coordination bond to a metal, the different side chain functionalities (in blue) can provide a variety of coordination sites to different metals. Side chains that contain N, O or S atoms (that have a lone pair of electrons) make excellent ligands for first row transition metals. Table from Inorganic Chemistry, Oxford, 7th Edition For example Histidine, which has and imidazole group as its functional side chain, has two potential coordination sites for a transition metal. Both N atoms (δ and ε in Figure 3) as mono-dentate donor atoms can coordinate to a metal, with this amino acid having a preference for Fe, Cu and Zn complexes. Figure 3 Cu-imidazole coordination Prosthetic groups https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 5/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 Not all proteins are made up of only amino acids, several contain what is known as a prosthetic group, which is essential a non-amino acids complex that is essential for the protein activity. The most well-known example of these is the porphyrin group, known as the Haem moiety (a characteristic part of the molecule), which is found in haemoglobin. This ligand has a -2 charge and acts as a tetra-dentate ligand through all four N atoms in a 16-membered atom ring. Another common prosthetic group is the corrin macrocyclic ligand, which has a slightly smaller ring size (15-membered atom ring). This ligand has a -1 charge but acts as a tetra-dentate ligand through its 4 nitrogen atoms, similar to porphyrin. If the prosthetic group contains a metal ion within the protein, it is called a metalloprotein. Common metals for the porphyrin and corrin prosthetic groups are Fe (Haemoglobin) and Co (Cobalamin) respectively. Figure 4 ChemDraw representations of the macrocyclic ligands porphyrin and corrin, with the active site of the metallo-protien Cobalamin. https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 6/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 1.3. Activity 1 Considering only the side chains of these five amino acids, which ones, if any, could serve as ligands to form transition metal complexes? https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 7/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 1.4. Oxygen carriers Myoglobin (Mb) and Haemoglobin (Hb) Mb and Hb are haem-iron proteins that transport oxygen around the body (Figure 5). Mb and each unit of Hb has a haem prosthetic group which is the active site that binds O2. Hb transports O2 in the blood of mammals and Mb carries the O2 to the muscles. The haem is connected to the protein via Histidine amino acids using its nitrogen atom to coordinate to the Fe centre. This leaves a vacant coordination site for O2 binding and transport. Figure 5 The structure of the myoglobin (LHS) and haemoglobin (RHS) both with their helice structures A simplified overall reaction between Mb and O2 could be depicted as: Or it can be structurally depicted as shown in Figure 6. https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 8/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 Figure 6 The active site of myglobin showing the reversible O2 coordination. Geometries and oxidation states of the Fe atoms are highlighted. Images adapted from Inorganic Chemistry, 7th addition, Oxford The Fe in deoxygenated myoglobin (Mb) is high-spin Fe2+ and it is in a square pyramidal geometry. Once it becomes oxygenated, formed by oxygen binding to the Fe centre, the metal undergoes a redox change via oxidation to Fe3+ and changes its geometry to octahedral. At this point, upon coordination of a molecule of O2 the Fe atom moves into the plane of the porphyrin macrocyclic ring. The overall reaction is reversible so as the O2 is released, the iron will revert back to its +2 resting state. The binding of oxygen on myoglobin can be followed by the difference in the IR stretching frequencies of the oxygen to oxygen bond. Effects of carbon monoxide Carbon monoxide is known as the silent killer. You often hear about this gas in the media from the misuse and under maintenance of old wall heaters and boilers. Its toxicity stems from its affinity for the haem moieties. CO binds to haem 200 times more strongly than O2 thus preventing O2 uptake causing the body to become starved of oxygen. Since both CO and O2 binding are equilibrium process, CO binding can be reversed by breathing in high concentrations of O2. If air contains ~20% O2 and 0.1% CO, [HbO2] = [HbCO]. Haemocyanin – a copper metalloprotein Haemocyanin functions similarly to haemoglobin, with a major difference being the metal at the centre of the prosthetic group. Where haemoglobin uses iron, Haemocyanin uses copper. This oxygen carrying molecule is found in molluscs and arthropods (snails, crabs, scorpions, spiders etc). Another major difference between haemocyanin and haemoglobin is the colour of the oxygenated species. Haemoglobin is red when oxygenated, whereas haemocyanin is blue (Figure 7). https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 9/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 Figure 7 Structure of haemocyanin and haemoglobin In terms of biological applications, the blood of the Horse-shoe crab, which contains haemocyanin, is a potent antibacterial and can be used to synthesis anti-clotting agents. Because of this, horse-shoe crab blood is harvested for medicinal purposes. Just one litre of this super blue blood goes for ~ $15,000! The active site of the haemocyanin is made up of two copper centres in the +1 oxidation state, each which are coordinated to three histidine ligands via their N atoms (Figure 8). Figure 8 Haemocyanin active site and O2 coordination Adapted from: Inorganic Chemistry, 7th edition, Oxford https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 10/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 1.5. Activity 2 d-orbital Splitting diagram Draw the d-orbital splitting diagram for Fe in oxy-Mb and identify whether it is high or low spin state. Nature of O2 Considering the IR stretching frequency of O2 in oxy-Mb is ~ 1107 cm-1 what is the most likely nature of O2 if the following IR data is known? IR data (cm-1) Neutral oxygen (O2) 1560 Superoxide (O2-) 1140 Peroxide (O22-) 800 Once you identify the most likely nature of O2 in oxy-Mb determine the number of unpaired electrons in this molecule of O2. https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 11/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 1.6. Zinc Zinc based enzymes Zinc is found in over 200 enzymes, so a 70 kg human will have approximately 2.3 g of zinc contained within their body. Zinc is more inclined to bind with oxygen or nitrogen donors. In most cases it prefers a coordination number of 4 and a tetrahedral geometry however, it can be 5 or 6 coordinate. Unlike Fe and Cu in the previous section, Zn does not change its oxidation state and is generally redox stable. Instead it acts as an acid- base catalyst in many of the enzymes active sites. Zn is usually found coordinated to histidine or cysteine amino acid residues. The large family of Zn enzymes include carbonic anhydrase, β-lactamase (responsible for penicillin resistance in bacteria) and alcohol dehydrogenase. Carbonic Anhydrase Carbonic anhydrase is a common Zn enzyme (Figure 9). It is found predominately in the red blood cells, and is responsible for the catalysis of the reversible hydration of CO2 to form the bicarbonate ion and a proton. This enzyme plays important roles in photosynthesis, respiration and pH control. The Zn centre is coordinated by three His-N ligands and one H2O molecule in a tetrahedral arrangement. Figure 9 The active site of carbonic anhydrase From Inorganic Chemistry, 7th edition, Oxford. The mechanism of action of carbonic anhydrase (Figure 10) is detailed below. A key feature is the acidity of the coordinated H2O molecule to the Zn metal centre (1), after deprotonation the HO- ion that is produced is sufficiently nucleophilic to attack a nearby CO2 (2) molecule. This attack results in a coordinated HCO3- ion (3) which is them released (4). https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 12/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 Figure 10 Mechanism of action of carbonic anhydrase https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 13/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 1.7. Metals in Medicine Metals in medicine Metals have been used historically for many years to combat a variety of diseases. These complexes coordinate to biological molecules much the same way as to regular small organic ligands. These element range across the entire periodic table, with many of them being transition metals (Figure 11). Figure 11 Periodic table showing the main elements in drugs and diagnostic agents Image from Inorganic Chemistry, 7th ed, Oxford Platinum in Medicine One well known example of a biological therapeutic metal complex is cisplatin (Figure 12), the platinum anti-cancer agent. Cisplatin is effective in the treatment of bladder, ovarian, cervical and testicular cancers, however it also has several negative drawbacks, including an array of side-effects such as nausea and kidney damage. Cisplatin is a square-planar complex which gets its name from the cis-arrangement of its ligands. It is injected intravenously and travels through the blood stream until it reaches the cancerous cells. When in the cell, the Cl- levels are quite low, so the cisplatin exchanges its chloride ligands with water, thus becoming a charged complex. Figure 12 shows the steps pf the reaction. Figure 12 Mechanism of transport of cisplatin from bloodstream to the DNA of a cancer cell Image adapted from Inorganic Chemistry 7th ed. Oxford It should be noted that the diaqua complex is considered the active species. https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 14/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 The cisplatin then binds to DNA bases and prevents transcription of that strand. It then reacts with an adjacent guanine base and causes the DNA strand to unwind, which then further inhibits replication. In fact, the two water ligands on the platinum are replaced by adjacent guanine bases (Figure 13 ) and not any other combination of DNA bases (Figure 14). This binding of the base results in the unwinding of DNA and cell replication inhibition. Figure 13 Structure of the complex formed from Pt(NH3)2 fragment from cisplatin and two adjacent guanine bases. The square planar geometry of Pt is highlighted. Image adapted from Inorganic Chemistry, 7th ed., Oxford Figure 14 The four common DNA bases A, G, T and C Despite the efficacy of cisplatin, it has highly undesirable side effects, in particular it can cause serious damage to the kidneys. Due to this several efforts have been made to design and synthesise Pt complexes that exhibit fewer side effects. Examples in clinical use include Carboplatin and Oxaliplatin both Pt2+ complexes that show reduced side effects (Figure 15). Figure 15 Two new Pt-anticancer drugs on the market with reduced side effects More recently the first orally administered Pt anti-cancer drug Satraplatin has been synthesised (Figure 16). This Pt4+ complex is an example of a 'pro-drug' - a compound that, by intention, has no activity until activated by entering the target environment - in this case cancer cells/tumour. Once Satraplatin enters the target cancer cells it is reduced from Pt4+ to Pt2+, losing its axial ligands to give the active, square planar Pt2+ form. https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 15/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 Figure 16 Satraplatin and its mode of action as a 'pro drug' https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 16/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 1.8. Metals in Imaging and Diagnostics Radioactive Transition Metals Radioactive transition metals have been used in nuclear medicine since the 1960s. The radiation produced by the ‘radiometals’ allows them to be followed very accurately. This quality makes them useful for medical diagnosis and treatment of disease. The radiometals are present at very low concentrations so that they do not perturb the biological system that is being monitored. The environment inside of the body provides multiple potential ligands for radiometals therefore complexes must be very stable with large formation constants (Kf) - see Week 9. Chromium - 51Cr Chromium-51 is an isotope of chromium that emits radiation useful for nuclear medicine. 51Cr is typically obtained from commercial sources as 51CrO42-. Reduction to Cr3+ followed by complexation by the hexadentate ligand EDTA4- produces [51Cr(EDTA)]- (Figure 17). [51Cr(EDTA)]- is injected into the blood stream and is used to test how well the renal system is working by monitoring the flow rate of filtered blood through the kidneys. Figure 17 Complexation of 51Cr by EDTA4- and its use as a renal flow diagnostic reagent Explore the 3D representation of the molecular structure of the two isomers of [Cr(EDTA)]- illustrated in this ChemTube 3D page (click the link). Using the controls located at the right hand corner of the image, explore the different dimensions to get a wider perspective to the shape. Copper - 64Cu Copper-64 is an isotope of copper that emits radiation useful for diagnostic imaging. The EDTA complex of Cu2+ is not useful for this purpose because the 64Cu will rapidly exchange with ligands in the body and ultimately accumulate in non-target organs such as the liver. More stable Cu2+ complexes are formed with ligands containing multiple donor atoms in a ring called macrocycles. Macrocyclic ligands exhibit particularly high affinity for metal ions. This is called the macrocyclic effect and follows the same principle as the chelate effect but the effect is further enhanced by the pre-organised conformation of the ligand for binding metal ions. Two such macrocyclic ligands H4DOTA (1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetic acid) and H3NOTA (1,4,7-triazacyclononane-1,4,7-triacetic acid ) are shown in Figure 18. https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 17/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 Figure 18 Macrocyclic ligands H4DOTA and H3NOTA Both Cu2+ macrocyclic complexes in Figure 19 have an octahedral molecular geometry. The Cu2+ ion is situated in the cavity of the tetraaza ring of DOTA with the two carboxylate oxygen donor atoms situated above and below the plane of the ring in the axial positions. The Cu2+ ion sits above the smaller macrocyclic NOTA cavity defined by the facial triaza plane and an opposite facial plane of three carboxylate oxygen donor atoms. The very large formation constants of these complexes make them suitable for nuclear medicine applications allowing them to reach their target site or organ without being metabolised and broken down by the body. Figure 19 Cu2+ complexes of [Cu(H2DOTA]- and [Cu(NOTA)]- https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 18/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 2. Summary In summary we have learnt that transition metals play a vital role for the body to function both in everyday life, and as medicines and diagnostic materials used to keep disease at bay. Biological inorganic chemistry uses a variety of ligands - such as amino acids and prosthetic groups, which like traditional inorganic metal complexes, heavily rely on the presence of heteroatoms (N, S, O) for coordination sites, enhancing their stability in the body. We have also looked at the development of new anti-cancer drugs, with reduced side effects buy simple modification of the ligand and showed how transition metal complexes can play a role to detect diseases. Overall bioinorganic chemistry will continue to play a vital role in the development of new transition metal medicines that will help us fight diseases and prolong out life. https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 19/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 3. Preparation quiz Now that you have completed the pre-workshop material, attempt the following preparation quiz. These 10 questions give you a chance to test your knowledge and practice the skills that were covered in this week's pre-workshop material. This material is essential for this week's workshops and may be applied in your laboratory classes. You have two attempts at each quiz and your highest attempt will count towards your final grade. Preparation quiz for Week 12 https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 20/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 4. Online lectures Week 12 Part A Week 12 Part These B have been automatically generated. As such, the captions Week 12 Part B quality is not 100% accurate. Accuracy may be affected by audio quality, topic under discussion and clarity of the speakers. Staff are not expected or required to edit or correct automatically- generated captions. It is best to not rely solely on captions when viewing video play_arrow content and to use them alongside other learning resources. Students who are registered with Disability Support Services should be in contact with them to discuss captioning if needed. Powered by Panopto get_app closed_caption fullscreen keyboard_arrow_up Week 12 Part These C have been automatically generated. As such, the captions Week 12 Part C quality is not 100% accurate. Accuracy may be affected by audio quality, topic under discussion and clarity of the speakers. Staff are not expected or required to edit or correct automatically- generated captions. It is best to not rely solely on captions when viewing video play_arrow content and to use them alongside other learning resources. Students who are registered with Disability Support Services should be in contact with them to discuss captioning if needed. Powered by Panopto get_app closed_caption fullscreen keyboard_arrow_up Week 12 Part D https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 21/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 Week 12 Part E Week 12 Part These F have been automatically generated. As such, the captions Week 12 Part F quality is not 100% accurate. Accuracy may be affected by audio quality, topic under discussion and clarity of the speakers. Staff are not expected or required to edit or correct automatically- generated captions. It is best to not rely solely on captions when viewing video play_arrow content and to use them alongside other learning resources. Students who are registered with Disability Support Services should be in contact with them to discuss captioning if needed. Powered by Panopto get_app closed_caption fullscreen keyboard_arrow_up Week 12 Part These G have been automatically generated. As such, the captions Week 12 Part G quality is not 100% accurate. Accuracy may be affected by audio quality, topic under discussion and clarity of the speakers. Staff are not expected or required to edit or correct automatically- generated captions. It is best to not rely solely on captions when viewing video play_arrow content and to use them alongside other learning resources. Students who are registered with Disability Support Services should be in contact with them to discuss captioning if needed. Powered by Panopto get_app closed_caption fullscreen keyboard_arrow_up Week 12 Part These H have been automatically generated. As such, the captions Week 12 Part H quality is not 100% accurate. Accuracy may be affected by audio quality, topic under discussion and clarity of the speakers. Staff are not expected or required to edit or correct automatically- generated captions. It is best to not rely solely on captions when viewing video play_arrow content and to use them alongside other learning resources. Students who are registered with Disability Support Services should be in contact with them to discuss captioning if needed. Powered by Panopto get_app closed_caption fullscreen keyboard_arrow_up https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 22/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 Week 12 Part These I have been automatically generated. As such, the captions Week 12 Part I quality is not 100% accurate. Accuracy may be affected by audio quality, topic under discussion and clarity of the speakers. Staff are not expected or required to edit or correct automatically- generated captions. It is best to not rely solely on captions when viewing video play_arrow content and to use them alongside other learning resources. Students who are registered with Disability Support Services should be in contact with them to discuss captioning if needed. Powered by Panopto get_app closed_caption fullscreen keyboard_arrow_up Online lecture slides can be downloaded from this link: Week 12 lecture slides https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 23/24 10/13/24, 8:05 PM Week 12 - Bioinorganic chemistry - workbook | MonashELMS1 5. Workshop CHM1022 Workshop These captions haveWeek been 12 automatically generated. As such, the CHM1022 Workshop Week 12 quality is not 100% accurate. Accuracy may be affected by audio quality, topic under discussion and clarity of the speakers. Staff are not expected or required to edit or correct automatically- generated captions. It is best to not rely solely on captions when viewing video play_arrow content and to use them alongside other learning resources. Students who are registered with Disability Support Services should be in contact with them to discuss captioning if needed. Powered by Panopto get_app closed_caption fullscreen keyboard_arrow_up Worksheets can be downloaded from these links: Week 12 worksheet Week 12 worksheet solutions https://learning.monash.edu/mod/book/tool/print/index.php?id=2780864 24/24