Biosynthesis


Biosynthesis, i.e., chemical synthesis occurring in biological contexts, is a term most often referring to multi-step, enzyme-catalyzed processes where chemical substances absorbed as nutrients serve as enzyme substrates, with conversion by the living organism either into simpler or more complex products. Examples of biosynthetic pathways include those for the production of amino acids, lipid membrane components, and nucleotides, but also for the production of all classes of biological macromolecules, and of acetyl-coenzyme A, adenosine triphosphate, nicotinamide adenine dinucleotide and other key intermediate and transactional molecules needed for metabolism. Thus, in biosynthesis, any of an array of compounds, from simple to complex, are converted into other compounds, and so it includes both the anabolism and catabolism of complex molecules. Biosynthetic processes are often represented via charts of metabolic pathways. A particular biosynthetic pathway may be located within a single cellular organelle, while others involve enzymes that are located across an array of cellular organelles and structures.

Elements of biosynthesis

Elements of biosynthesis include: precursor compounds, chemical energy, and catalytic enzymes which may need coenzymes. These elements create monomers, the building blocks for macromolecules. Some important biological macromolecules include: proteins, which are composed of amino acid monomers joined via peptide bonds, and DNA molecules, which are composed of nucleotides joined via phosphodiester bonds.

Properties of chemical reactions

Biosynthesis occurs due to a series of chemical reactions. For these reactions to take place, the following elements are necessary:
  • Precursor compounds: these compounds are the starting molecules or substrates in a reaction. These may also be viewed as the reactants in a given chemical process.
  • Chemical energy: chemical energy can be found in the form of high energy molecules. These molecules are required for energetically unfavourable reactions. Furthermore, the hydrolysis of these compounds drives a reaction forward. High energy molecules, such as ATP, have three phosphates. Often, the terminal phosphate is split off during hydrolysis and transferred to another molecule.
  • Catalysts: these may be for example metal ions or coenzymes and they catalyze a reaction by increasing the rate of the reaction and lowering the activation energy.
In the simplest sense, the reactions that occur in biosynthesis have the following format:
Some variations of this basic equation which will be discussed later in more detail are:
  1. Simple compounds which are converted into other compounds, usually as part of a multiple step reaction pathway. Two examples of this type of reaction occur during the formation of nucleic acids and the charging of tRNA prior to translation. For some of these steps, chemical energy is required:
  2. ::+ATP <=> + PP_i
  3. Simple compounds that are converted into other compounds with the assistance of cofactors. For example, the synthesis of phospholipids requires acetyl CoA, while the synthesis of another membrane component, sphingolipids, requires NADH and FADH for the formation the sphingosine backbone. The general equation for these examples is:
  4. :: + ->
  5. Simple compounds that join to create a macromolecule. For example, fatty acids join to form phospholipids. In turn, phospholipids and cholesterol interact noncovalently in order to form the lipid bilayer. This reaction may be depicted as follows:
  6. :: + ->

    Lipid

Many intricate macromolecules are synthesized in a pattern of simple, repeated structures. For example, the simplest structures of lipids are fatty acids. Fatty acids are hydrocarbon derivatives; they contain a carboxyl group "head" and a hydrocarbon chain "tail". These fatty acids create larger components, which in turn incorporate noncovalent interactions to form the lipid bilayer.
Fatty acid chains are found in two major components of membrane lipids: phospholipids and sphingolipids. A third major membrane component, cholesterol, does not contain these fatty acid units.

Eukaryotic phospholipids

The foundation of all biomembranes consists of a bilayer structure of phospholipids. The phospholipid molecule is amphipathic; it contains a hydrophilic polar head and a hydrophobic nonpolar tail. The phospholipid heads interact with each other and aqueous media, while the hydrocarbon tails orient themselves in the center, away from water. These latter interactions drive the bilayer structure that acts as a barrier for ions and molecules.
There are various types of phospholipids; consequently, their synthesis pathways differ. However, the first step in phospholipid synthesis involves the formation of phosphatidate or diacylglycerol 3-phosphate at the endoplasmic reticulum and outer mitochondrial membrane. The synthesis pathway is found below:
The pathway starts with glycerol 3-phosphate, which gets converted to lysophosphatidate via the addition of a fatty acid chain provided by acyl coenzyme A. Then, lysophosphatidate is converted to phosphatidate via the addition of another fatty acid chain contributed by a second acyl CoA; all of these steps are catalyzed by the glycerol phosphate acyltransferase enzyme. Phospholipid synthesis continues in the endoplasmic reticulum, and the biosynthesis pathway diverges depending on the components of the particular phospholipid.

Sphingolipids

Like phospholipids, these fatty acid derivatives have a polar head and nonpolar tails. Unlike phospholipids, sphingolipids have a sphingosine backbone. Sphingolipids exist in eukaryotic cells and are particularly abundant in the central nervous system. For example, sphingomyelin is part of the myelin sheath of nerve fibers.
Sphingolipids are formed from ceramides that consist of a fatty acid chain attached to the amino group of a sphingosine backbone. These ceramides are synthesized from the acylation of sphingosine. The biosynthetic pathway for sphingosine is found below:
As the image denotes, during sphingosine synthesis, palmitoyl CoA and serine undergo a condensation reaction which results in the formation of 3-dehydrosphinganine. This product is then reduced to form dihydrospingosine, which is converted to sphingosine via the oxidation reaction by FAD.

Cholesterol

This lipid belongs to a class of molecules called sterols. Sterols have four fused rings and a hydroxyl group. Cholesterol is a particularly important molecule. Not only does it serve as a component of lipid membranes, it is also a precursor to several steroid hormones, including cortisol, testosterone, and estrogen.
Cholesterol is synthesized from acetyl CoA. The pathway is shown below:
More generally, this synthesis occurs in three stages, with the first stage taking place in the cytoplasm and the second and third stages occurring in the endoplasmic reticulum. The stages are as follows:

Nucleotides

The biosynthesis of nucleotides involves enzyme-catalyzed reactions that convert substrates into more complex products. Nucleotides are the building blocks of DNA and RNA. Nucleotides are composed of a five-membered ring formed from ribose sugar in RNA, and deoxyribose sugar in DNA; these sugars are linked to a purine or pyrimidine base with a glycosidic bond and a phosphate group at the 5' location of the sugar.

Purine nucleotides

The DNA nucleotides adenosine and guanosine consist of a purine base attached to a ribose sugar with a glycosidic bond. In the case of RNA nucleotides deoxyadenosine and deoxyguanosine, the purine bases are attached to a deoxyribose sugar with a glycosidic bond. The purine bases on DNA and RNA nucleotides are synthesized in a twelve-step reaction mechanism present in most single-celled organisms. Higher eukaryotes employ a similar reaction mechanism in ten reaction steps. Purine bases are synthesized by converting phosphoribosyl pyrophosphate to inosine monophosphate, which is the first key intermediate in purine base biosynthesis. Further enzymatic modification of IMP produces the adenosine and guanosine bases of nucleotides.
  1. The first step in purine biosynthesis is a condensation reaction, performed by glutamine-PRPP amidotransferase. This enzyme transfers the amino group from glutamine to PRPP, forming 5-phosphoribosylamine. The following step requires the activation of glycine by the addition of a phosphate group from ATP.
  2. GAR synthetase performs the condensation of activated glycine onto PRPP, forming glycineamide ribonucleotide.
  3. GAR transformylase adds a formyl group onto the amino group of GAR, forming formylglycinamide ribonucleotide .
  4. FGAR amidotransferase catalyzes the addition of a nitrogen group to FGAR, forming formylglycinamidine ribonucleotide.
  5. FGAM cyclase catalyzes ring closure, which involves removal of a water molecule, forming the 5-membered imidazole ring 5-aminoimidazole ribonucleotide.
  6. N5-CAIR synthetase transfers a carboxyl group, forming the intermediate N5-carboxyaminoimidazole ribonucleotide.
  7. N5-CAIR mutase rearranges the carboxyl functional group and transfers it onto the imidazole ring, forming carboxyamino- imidazole ribonucleotide. The two step mechanism of CAIR formation from AIR is mostly found in single celled organisms. Higher eukaryotes contain the enzyme AIR carboxylase, which transfers a carboxyl group directly to AIR imidazole ring, forming CAIR.
  8. SAICAR synthetase forms a peptide bond between aspartate and the added carboxyl group of the imidazole ring, forming N-succinyl-5-aminoimidazole-4-carboxamide ribonucleotide.
  9. SAICAR lyase removes the carbon skeleton of the added aspartate, leaving the amino group and forming 5-aminoimidazole-4-carboxamide ribonucleotide.
  10. AICAR transformylase transfers a carbonyl group to AICAR, forming N-formylaminoimidazole- 4-carboxamide ribonucleotide.
  11. The final step involves the enzyme IMP synthase, which performs the purine ring closure and forms the inosine monophosphate intermediate.