Structural Biochemistry/Inorganic Chemistry

Importance of Inorganic Chemistry in Biochemistry: Bioinorganic Chemistry

Although biochemistry generally focuses on the reactions and interactions of biological and organic molecules within the body, the roles and interactions of various inorganic molecules with the macromolecules in the body are just as important. Of all the elements known, only a few are essential for living organisms: Hydrogen (H), Carbon (C), Nitrogen (N), Oxygen (O), Sodium (Na), Phosphorus (P), Sulfur (S), Chlorine (Cl), Potassium (K), and Calcium (Ca). Additionally, a small amount of trace elements are essential for certain subsets of organisms. These elements include Lithium (Li), Beryllium (Be), the transition metals Vanadium (V), Chromium (Cr), Manganese (Mn), Iron (Fe), Cobalt (Co), Nickel (Ni), Copper (Cu), Zinc (Zn), and Molybdenum (Mo), and the nonmetals Selenium (Se) and Iodine (I).

As a general overview, metal ions have varying roles in the body. Some examples of the metal ions’ roles are:

1. Linking distant residues or parts of the amino acida in the proteins together.
2. Mediating interactions between the protein and a ligand.
3. Positioning themselves in the active sites of the macromolecules as nucleophilic catalysts or as a key component in the electron transfer chain.

There are six major elements important to providing the building blocks for nucleic acids, proteins, lipids, etc. They are:

• Sulfur
• Phosphorus
• Nitrogen
• Oxygen
• Carbon
• Hydrogen

It would appear logical that numerous metal ions would be able to fulfill the biological processes. However, the biological processes require a specific metal in order to proceed because of their unique combination of properties such as specific crystal field stabilization energy, complex conformation, and electron transition states. For example:

• coagulation cascade: Ca²⁺ ions
• protein biosynthesis: Mg²⁺ ions
• biomineralization (producing minerals to harden the existing tissues): Ca²⁺, magnesium, iron, etc.
• energy storage: phosphorous as inorganic phosphate P_i, Na⁺, K⁺, iron, etc.
• signaling: Ca²⁺, boron, nitrogen, oxygen
• Lewis acid-base catalysis: zinc, iron, manganese
• numerous proteins, oxidative processes, and enzymes: Zn²⁺ ion

Macromolecules

Nucleic Acids

Nucleic acids are polymers made of nucleotides connected via phosphate-sugar backbones. There are two kinds of nucleic acids ribonucleic acid (RNA) and deoxyribonucleic acid (DNA). A nucleotide is made up of a 5-membered sugar (ribose or deoxyribose) which is connected to a nitrogenous base (guanine, adenine, thymine, cytosine, uracil) and phosphorous group(s). DNA is made up of nucleotides that have guanine, adenine, thymine, and cytosine bases whereas RNA is made up of nucleotides that have guanine, adenine, uracil, and cytosine bases. The nucleotides are attached to each other via a phosphate group along the 5'-3' carbon side of the sugar. In addition, DNA is usually a double-stranded molecule whereas RNA usually is a single-stranded molecule.

"Zinc Fingers" protein forming a complex with DNA

Deoxyribonucleic Acid (DNA)

DNA is a double-helix structure formed by the intertwining of two DNA strands in which the phosphate group is located on the outside of the molecule whereas the nitrogenous bases are inside the structure and are connected via hydrogen bonds and stabilized by Van der Waals forces, hydrophobic effects, and charge-charge repulsion. DNA binds metal ions to the phosphate groups and the electron donor groups in the nitrogenous bases. By binding to the negatively charged phosphate groups, the metal ions neutralize the negative charges on DNA, thereby stabilizing the double-helical structure of the DNA. High concentrations of metal ions can be deleterious though. If there is a high metal ion concentration, then less stabilization is required by hydrogen bonding between the nitrogenous bases which can lead to mis-pairing of bases and errors during transcription.

Ribonucleic Acid (RNA)

RNA polymerase bound to DNA and RNA through use of a Magnesium²⁺ ion.

Metal ions bind not only with DNA, but also with RNA. Metal ions interact with the phosphate groups and the electron donor groups in the RNA molecule. This interaction is important because it gives structural stability to the RNA. In addition to this contribution, metal ions interact with ribozymes. By nature, RNA is compact, stable, and folded. They are made of:

1. Ribosomal RNA (rRNA) --- their duty is to catalyze and regulate protein synthesis
2. Small nuclear RNAs molecules --- involved in the nucleus
3. Signal recognition particle --- transfers the proteins through the membranes of the cell

In all of these RNAs, metal ions play an essential role in the RNA's structure, formation and catalytic mechanisms -- this are explained in more detail directly below:

The pathway for the way the RNA folds is as follows: keep in mind that this is a simplified pathway, but works for our purposes. First, the RNA changes from a coil to a secondary structure. The second step is the progression to the tertiary structure. In tertiary structures, the long-range interactions determine the tertiary structure of the nucleic acid.

Because of the phosphate sugar backbone, metal ions play a heavy part in the interactions that RNA goes through to fold and function. Different metal ions with different charges play different charges in various roles of the transformation. Ions with a +1 charge have a part in the charge-screening. This allows the RNA molecules transform to the secondary structure. The tertiary structures of the RNA molecules are stabilized, not with monovalent ions, but with metal ions with two charges.

Holistically speaking, the formation of RNA's tertiary structure is contingent on four different criteria: (a) the RNA sequence, (b) metal ion identity, (c) metal ion concentration, and (d) the presence of RNA binding proteins. The preferred metal is Mg²⁺ because Mg²⁺ not only helps with stabilizing the tertiary structures, but also helps the RNA bind to sites of high affinity. However, other metals such as K⁺, Ca²⁺, Mn²⁺, Cd²⁺, Na⁺ and Li⁺ will also suffice. However, their range of reactivity only works for certain RNAs. However, overall, they are vital for RNA metabolism. Trivalent ions besides organic protonated ions are not used.

There are several types of metal ion binding to RNA known:
(a) Diffuse Binding -- performed and done by cations. They are vital to make secondary and tertiary structures.
(b) Site-bound outer-sphere binding of magnesium hexahydrate ion: Water ligands bridge the metal ions and the coordinating atoms on the RNA nucleobase or backbone.
(c) Site-bound inner-sphere binding of Mg²⁺ to the RNA -- The inner-sphere bound metal ions such as Mg²⁺ are involved in RNA formation and function.

Proteins

protein are molecules that perform the many important functions of the cell that keep it alive. Inorganic molecules and ions are a key part of many of these proteins and their interactions with other molecules. Metal ions can influence both the folding processes and the final structures of many important proteins.

Examples

Hemoglobin and Myoglobin

Iron Complex in Hemoglobin

Hemoglobin[[|]] and Myoglobin [[|]]are both oxygen-transport proteins that use metal ions to help carry out their functions. After their polypeptide chains have been sequenced, they bind with Fe²⁺ ions to form their final structures.

• Wikipedia-Hemoglobin
• Wikipedia-Myoglobin

Sodium Potassium Ion Pump

The Sodium Potassium Ion Pump is used to pump sodium ions out of a cell while at the same time pumping potassium ions in. This function can regulate a number of important cell properties, including the size of the cell and the amount of positive charge inside the cell relative to the outside (known as the resting potential).

• Wikipedia-Sodium Potassium Ion Pump

Chlorophyll

File:HEMOGLOBIN CHLOROPHYLL.gif

Heme and Chlorophyll Structures

Chlorophyll is the pigment in many plants that gives them their green color and allows them to create their food from sunlight. Chlorophyll uses a Mg²⁺ ion to start the light reactions of photosynthesis. Chlorophyll a and chlorophyll b are the two different types of chlorophyll that are found in plants. Their structure consists of a porphyrin ring with a central magnesium ion and a long hydrophobic side chain. The difference in the side chain allows chlorophyll to absorb light at different wavelengths. The hydrocarbon tail that is attached to the porphyrin ring makes chlorophyll fat-soluble and insoluble in water.

• Wikipedia-Chlorophyll

More Proteins that contain metals

Fe (heme): peroxidase, catalase, cytochrome P450, cytochrome c

Fe (without heme): ferredoxin, hemerythrin

Hemerythrin without heme

Cu: tyrosinase, nitrite reductase, amine oxidase

ZnII: carbonic anhydrase, carboxypeptidase, DNA polymerase

MgII: DNA polymerase

For more information ---> Miessler and Tarr. Inorganic Chemistry. 3rd ed. Pearson Prentice Hall: 2004.

Carbohydrates

Carbohydrates form complexes with many metal ions. The hydroxyl group carries a slight negative charge which is increased if the hydrogen atom is deprotonated. This allows carbohydrates to attach to metal ions which carry positive charges through ionic interactions[[|]].

Inorganic ions can also can also oxidize or reduce carbohydrates, determining their reactivity. Carbohydrates can be placed in a cupric ion solution. The ones that react can exist as a ketone or an aldehyde and called reducing sugars. These sugars react readily with many molecules. Those that do not react are non-reducing sugars.

Example

Calcium

In biological systems, carbohydrates have been observed with calcium. Studies show that in an aqueous solution calcium binds to ionic or uncharged carbohydrates. While there is no hard evidence, many believe that carbohydrates may have a role in transporting calcium, calcification, or storage of calcium.

Lipids

Lipids are hydrophobic molecules which in the case of fats and oils have as building blocks fatty acid and triglycerides; other lipids are steroids and waxes; phosphorylated lipids are the major component of plasma membrane.Link label Page text.

Inorganic compounds such as PO₄^3- and NaOH play important role in understanding reactions involving macromolecules and their uses.

Examples

phosphate in phospholipids.

phosphates play a major role in the formation of the lipid bilayer of the plasma membrane.Attaching to fatty acid,they form the hydrophilic end of the bilayer whereas the lipid part form the hydrophobic part.

Formation of soap, a mixture of sodium salts of different fatty acids. If the fatty acid salt has potassium rather than sodium, a softer lather is the result.

Soap is produced by a saponification or basic hydrolysis reaction of a fat or oil. Currently, sodium carbonate or sodium hydroxide is used to neutralize the fatty acid and convert it to the salt.

General overall hydrolysis reaction:

fat + NaOH ---> glycerol + sodium salt of fatty acid''

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