1 Introduction to Bioinorganic chemistry Unit 1 PDF

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Introduction of Bio-inorganic Chemistry...

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31-08-2018

Lecture Course Title Date

:1 :Bioinorganic chemistry and metalloenzymes. :2nd August 2018

Course code

:CHM 413

Introduction to Bioinorganic chemistry

Instructor :Dr. Pankaj Kumar Koli

Detailed Syllabus Unit-I Essential and trace metal ions in biological system. Deficiency/excess of Mn, Co, and Zn metal ions. Structure of chlorophyll, Photosynthesis, Photo system I and Photo system II. Unit-II Metalloenzymes; cytochromes and iron-sulphur proteins, nitrogen fixation, Zinc enzymes; carboxypeptidase, carbonic anhydrase. Iron enzymes-catalase and peroxidase. Unit-III General aspects of chemistry of dioxygen, Fe, Cu and Co. Nature of M-O2 linkage, heme proteins, molecular mechanism of oxygenases, Copper enzyme–superoxide dismutase. Cobalt enzyme; Cyanocobalamin. Biochemical bases of essential metal deficiency with special reference to Cu, Zn. Unit-IV Complexes of transition metal (Pt) as anticancer agent, mechanism of action. Toxic effect of Pt complexes to human body. Carbonic anhydrase and its mechanism of action super oxide dismutase. Mechanism of dismulation of super oxide ion.

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Books Recommended And Study Materials 1. Principles of Bioinorganic Chemistry, S.J. Lippard and J.M. Berg, University Science Books. 2. Bioinorganic Chemistry, I. Bertini, H.B. Gray, S.J. Lippard and J.S. Valentine, University Science Books. 3. Inorganic Biochemistry, vols I and II. ed., G.L. Eichhorn, Elsevier. 4. Progress in Inorganic Chemistry, Vols. 18 and 38 ed. J.J. Lippard, Eiley. 5. Inorg. Chemistry by Shriver Alkem Oxford University Press. 6. Modern Inorg. Chemistry by W. Jolly, 2nd Edition Mc Graw Hill Inc. 7. Bioinorganic Chemistry by A.K. Das CBS Publication & distribution.

Bioinorganic Chemistry: A New field

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Periodic table of Life

BioInorganic chemistry Study of Inorganic elements in the living systems

Sodium potassium pump (1/5th of all the ATP used)

Hemoglobin Myoglobin Cytochromes Ferredoxin

Vit B12

Hemocyanin

Carbonic anhydrase Carboxypeptidase

Xanthine Oxidase Aldehyde Oxidase

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Important roles metals play in biochemistry 1. Regulatory Action

Sodium potassium channels and pump

Na, K

Nerve signals and impulses, action potential, muscle contraction

2. Structural Role

Calcium in bones, teeth

Ca, Mg

provide strength and rigidity

3. Electron transfer agents

Cytochromes: redox intermediates

Fe2+/Fe3+

membrane-bound proteins that contain heme groups and carry out electron transport in Oxidative phosphorylation

4. Metalloenzymes

Carbonic anhydrase, Carboxypeptidase

Zn

biocatalysts, CO2 to HCO3 −, protein digestion

5. Oxygen carriers and storage Fe, Cu

Hemoglobin, Myoglobin, Hemocyanin 18 times more energy from glucose in presence of O2

6. Metallo coenzymes Co

Vitamin B 12 biomethylation

● Mammals are believed to use only 25 of the known elements ● 96% of our body is made up of C,H,N,O ● Even Though some elements are present in very small quantities in body, they maintains essential functions.

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Transition Metals in Biomolecules Iron Most abundant metal in biology, used by all plants and animals including bacteria. Some roles duplicated by other metals, while others are unique to Fe. Iron use has survived the evolution of the O2 atmosphere on earth and the instability of Fe(II) with respect to oxidation to Fe(III). Zinc Relatively abundant metal. Major concentration in metallothionein (which also serves as a reservoir for other metals, e.g. Cd, Cu, Hg). Many well characterized Zn proteins, including redox proteins, hydrolases and nucleic acid binding proteins. Copper Often participatse together with Fe in proteins or has equivalent redox roles in same biological reactions. Reversible O2 binding, O2 activation, electron transfer, O2- dismutation (SOD), NO biosynthesis. Cobalt Unique biological role in cobalamin (B12-coenzymes) isomerization reactions. Manganese Critical role in photosynthetic reaction centers, and SOD enzymes. Molybdenum Central role in nitrogenase enzymes catalyzing N2 NH3, NO3 NH3 Chromium, Vanadium and Nickel Small quantities, uncertain biological roles. Sugar metabolism (Cr); Ni only in plants and bacteria (role in CH4 production) and SOD enzymes.

Structure of a metallo-protein : A metal complex perspective Spiral - α helix form of protein

Tape - β Pleated sheet form of protein

Prosthetic groups – A metal complex positioned in a crevice. Some of the ligands for this complex or some times all f the ligands are provided by the side groups of the amino acid units. The geometry around the metal and bond distances and angles are decided by the protein unit

Myoglobin

Carbonic anhydrase

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Metalloenzymes and Oxygen carriers = Protein + Cofactor A cofactor is a non-protein chemical compound that is bound to a protein and is required for the protein's biological activity. These proteins are commonly enzymes. Cofactors are either organic or inorganic. They can also be classified depending on how tightly they bind to an enzyme, with loosely-bound or protein-free cofactors termed coenzymes and tightly-bound cofactors termed prosthetic groups. Porphyrins with different are a metals at its centre common prosthetic group in bioinorganic chemistry

Cytochrome C

Coenzyme B12

Hemocyanin

Myoglobin

Chlorophyll

ProtoporphyrinIXandHeme

15 different ways to arrange the substituents around the porphyrin. Only one isomer, protopophyrin IX is found in the living system. Porphyrins are planar and aromatic

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Proteins–consistsofdifferentaminoacidsinaspecificsequenceconnectedbythepeptidebond–

A few important amino acids relevant to the present course

HISTDINE This amino acid has a pKa of 6.5. This means that, at physiologically relevant pH values, relatively small shifts in pH will change its average charge. Below a pH of 6, the imidazole ring is mostly protonated.

GLUTAMIC ACID has carboxylic acid functional group which is hydrophilic, has pKa of 4.1 and exists in its negatively charged deprotonated carboxylate form at physiological pH ranging from 7.35 to 7.45.

VALINE is a branched-chain amino acid having a hydrophobic isopropyl R group. In sickle-cell disease, valine substitutes for the hydrophilic amino acid, glutamic acid, in hemoglobin. Valine is hydrophobic

SERINE is an amino acid having a CH2OH side group. By virtue of the hydroxyl group, serine is classified as a polar amino acid. Serine was first obtained from silk protein, a particularly rich source, in 1865.

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Theprimarystructureofaprotein

Thefourlevelsofproteinstructure

Hbondbetweensidechains, hydrophobicinteractions, disulfurlinkages,electrostatic interactions

Seeyoutube video“proteinstructure”Univ ofSurrey’

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Hemoglobin‐ aquaternarystructureofaprotein

4 units, Each unit has a prosthetic group (heme) embedded in a crevice and partly coordinated by histidine units

Inorganic Active site / Prosthetic group

In molecular biology, the active site (prosthetic group) is part of an enzyme where substrates bind and undergo a chemical reaction. It can perform its function only when it is associated with the protein unit Heme in Myoglobin (O2 storage)

Ferredoxin (e transfer)

Nitrogen Fixation Carbonic anhydrase Enzyme

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Inorganic Prosthetic group of three well known oxygen carriers

Presentin Vertebrates

Presentin molluscs

Presentinsomesea worms

Hemoglobin S (Sickle Cell Anaemia)

Sickle-cell anaemia is caused by a mutation in the β-globin chain of haemoglobin, causing a hydrophilic amino acid glutamic acid to be replaced with the hydrophobic amino acid valine. In areas where malaria is a problem, people's chances of survival actually increase if they carry sickle-cell trait (Carrier). The malaria parasite has a complex life cycle and spends part of it in red blood cells. In a carrier, the presence of the malaria parasite causes the red blood cells with defective haemoglobin to rupture prematurely, making the plasmodium unable to reproduce. The polymerization of Hb S affects the ability of the parasite to digest Hb.

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Role in Medicine and diagnosis Some very toxic metals (e.g. Hg and As) were used to treat syphilis and other infections in the past. Hg is still used today: amalgam, skin lightening cream, eye drops, nasal sprays. Nowadays, inorganic pharmaceuticals are becoming more and more important in medicine

Cardiolyte is a radioactive imaging agent to assess blood flow through heart. It is an Isonitrile complex which uses of 99mTc (generated from 98Mo by irradiation with neutrons; t1/2 = 6 h). Cardiolyte’s advantages: Readily taken up by blood and tissues. Rapid clearance without evidence of metabolism

Chemistry at active site of Hemerythrin (Hr)

Hemerythrin

proton-coupled electron transfer evidence for proton transfer comes from resonance Raman work

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Early Structural Models for Deoxy-hemerythrin

None does the chemistry of the protein!

Functionally relevant model of Hemerythrin

O-Ligand

Product matches protein Mössbauer, resonance Raman, UV-vis spectra Inorg. Chem. 2001, 40, 4662-4673

10.1021/ic010076b

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