Biosynthesis (also called biogenesis or anabolism) is a multi-step, enzyme-catalyzed process where substrates are converted into more complex products. In biosynthesis, simple compounds are modified, converted into other compounds, or joined together to form macromolecules. This process often consists of metabolic pathways. Some of these biosynthetic pathways are located within a single cellular organelle, while others involve enzymes that are located within multiple cellular organelles. Examples of these biosynthetic pathways include the production of lipid membrane components and nucleotides.
The prerequisite elements for biosynthesis include: precursor compounds, chemical energy (e.g. ATP), and catalytic enzymes which may require coenzymes (e.g.NADH, NADPH). 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.
- 1 Properties of chemical reactions
- 2 Membrane lipids
- 3 Nucleotides
- 4 DNA
- 5 Amino acids
- 6 Proteins
- 7 Diseases associated with macromolecule deficiency
- 8 See also
- 9 References
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 unfavorable 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.
- Catalytic enzymes: These molecules are special proteins that catalyze a reaction by increasing the rate of the reaction and lowering the activation energy.
- Coenzymes or cofactors: Cofactors are molecules that assist in chemical reactions. These may be metal ions, vitamin derivatives such as NADH and acetyl CoA, or non-vitamin derivatives such as ATP. In the case of NADH, the molecule transfers a hydrogen, whereas acetyl CoA transfers an acetyl group, and ATP transfers a phosphate.
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. 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, shingolipids, requires NADH and FADH for the formation the sphingosine backbone. The general equation for these examples is:
3. Simple compounds that join together to create a macromolecule. For example, fatty acids join together to form phopspholipids. In turn, phospholipids and cholesterol interact noncovalently in order to form the lipid bilayer. This reaction may be depicted as follows:
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.
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.
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 dehydrosphingosine. This product is then reduced to form dihydrospingosine, which is converted to sphingosine via the oxidation reaction by FAD.
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.
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:
- 1. The synthesis of isopentenyl pyrophosphate, the “building block” of cholesterol
- 2. The formation of squalene via the condensation of six molecules of isopentenyl phosphate
- 3. The conversion of squalene into cholesterol via several enzymatic reactions
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.
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 (PRPP) to inosine monophosphate (IMP), which is the first key intermediate in purine base biosynthesis. Further enzymatic modification of IMP results with adenosine and guanosine bases of nucleotides.
- 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.
- GAR synthetase performs the condensation of activated glycine onto PRPP, forming glycineamide ribonucleotide (GAR).
- GAR transformylase adds a formyl group onto the amino group of GAR, forming formylglycinamide ribonucleotide (FGAR).
- FGAR amidotransferase catalyzes the addition of a nitrogen group to FGAR, forming formylglycinamidine ribonucleotide (FGAM).
- FGAM cyclase catalyzes ring closure, which involves removal of a water molecule, forming the 5-membered imidazole ring 5-aminoimidazole ribonucleotide (AIR).
- N5-CAIR synthetase transfers a carboxyl group, forming the intermediate N5-carboxyaminoimidazole ribonucleotide (N5-CAIR).
- N5-CAIR mutase rearranges the carboxyl functional group and transfers it onto the imidazole ring, forming carboxyamino- imidazole ribonucleotide (CAIR). The two step mechanism of CAIR formation, from AIR, is mostly found in single celled organisms. Higher eukaryotes contain the enzyme AIR carboxylase that transfers a carboxyl group directly to AIR imidazole ring, forming CAIR.
- 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 (SAICAR).
- SAICAR lyase removes the carbon skeleton of the added aspartate, leaving the amino group and forming 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR).
- AICAR transformylase transfers a carbonyl group to AICAR, forming N-formylaminoimidazole- 4-carboxamide ribonucleotide (FAICAR).
- The final step involves the enzyme, IMP synthase, which performs the purine ring closure and forms the inosine monophosphate (IMP) intermediate.
Other DNA and RNA nucleotide bases which are linked to the ribose sugar via a glycosidic bond are thymine, cytosine and uracil (which is only found in RNA). Uridine monophosphate biosynthesis involves an enzyme that is located in the mitochondrial inner membrane and multifunctional enzymes that are located in the cytosol.
- The first step involves the enzyme carbamoyl phosphate synthase combining glutamine with CO2 in an ATP dependent reaction to form carbamoyl phosphate.
- Aspartate carbamoyltransferase condenses carbamoyl phosphate with aspartate to form uridosuccinate.
- Dihydroorotase performs ring closure, a reaction that loses water, to form dihydroorotate.
- Dihydroorotate dehydrogenase, located within the mitochondrial inner membrane, oxidizes dihydroorotate to orotate.
- Orotate phosphoribosyl hydrolase (OMP pyrophosphorylase) condenses orotate with PRPP to form orotidine-5’-phosphate.
- OMP decarboxylase catalyzes the conversion of orotidine-5’-phosphate to UMP.
After the uridine nucleotide base is synthesized, the other bases, cytosine and thymine are synthesized. Cytosine biosynthesis is a two-step reaction which involves the conversion of UMP to UTP. Phosphate addition to UMP is catalyzed by a kinase enzyme. The enzyme CTP synthase catalyzes the next reaction step: the conversion of UTP to CTP by transferring an amino group from glutamine to uridine to form the cytosine base of CTP. The mechanism, which depicts the reaction UTP + ATP + glutamine ⇔ CTP + ADP + glutamate, is below:
Cytosine is a nucleotide that is present in both DNA and RNA. However, uracil is only found in RNA. Therefore, after UTP is synthesized, it is must be converted into a deoxy form to be incorporated into DNA. This conversion involves the enzyme ribonucleoside triphosphate reductase. This reaction that removes the 2’-OH of the ribose sugar to generate deoxyribose is not affected by the bases attached to the sugar. This non-specificity allows ribonucleoside triphosphate reductase to convert all nucleotide triphosphates to deoxyribonucleotide by a similar mechanism.
In contrast to uracil, thymine bases are found mostly in DNA, not RNA. Cells do not normally contain thymine bases that are linked to ribose sugars in RNA. This indicates that cells only synthesize deoxyribose-linked thymine. The enzyme thymidylate synthetase is responsible for synthesizing tymine residues from dUMP to dTMP. This reaction transfers a methyl group onto the uracil base of dUMP to generate dTMP. The thymidylate synthase reaction, dUMP + 5,10-methylenetetrahydrofolate ⇔ dTMP + dihydrofolate, is shown to the right.
DNA is composed of nucleotides that are joined by phosphodiester bonds. DNA synthesis, which takes place in the nucleus, is a semiconservative process, which means that the resulting DNA molecule contains an original strand from the parent structure and a new strand. DNA synthesis is catalyzed by a family of DNA polymerases that require four deoxynucleoside triphosphates, a template strand, and a primer with a free 3’OH in which to incorporate nucleotides.
In order for DNA replication to occur, a replication fork is created by enzymes called helicases which unwind the DNA helix. Topoisomerases at the replication fork remove supercoils caused by DNA unwinding, and single-stranded DNA binding proteins maintain the two single-stranded DNA templates stabilized prior to replication.
DNA synthesis is initiated by the RNA polymerase, primase, which makes an RNA primer with a free 3’OH. This primer is attached to the single-stranded DNA template, and DNA polymerase elongates the chain by incorporating nucleotides; DNA polymerase also proofreads the newly synthesized DNA strand.
During the polymerization reaction catalyzed by DNA polymerase, a nucleophilic attack occurs by the 3’OH of the growing chain on the innermost phosphorus atom of a deoxynucleoside triphosphate; this yields the formation of a phosphodiester bridge that attaches a new nucleotide and releases pyrophosphate.
Two types of strands are created simultaneously during replication: the leading strand, which is synthesized continuously and grows towards the replication fork, and the lagging strand, which is made discontinuously in Okazaki fragments and grows away from the replication fork. Okazaki fragments are covalently joined by DNA ligase to form a continuous strand. Then, to complete DNA replication, RNA primers are removed, and the resulting gaps are replaced with DNA and joined via DNA ligase.
A protein is a polymer that is composed from amino acids that are linked by peptide bonds. There are more than 300 amino acids found in nature of which only twenty, known as the standard amino acids, are the building blocks for protein. Only green plants and most microbes are able to synthesize all of the 20 standard amino acids that are needed by all living species. Mammals can only synthesize ten of the twenty standard amino acids. The other amino acids, valine, methionine, leucine, isoleucine, phenylalanine, lysine, threonine and tryptophan for adults and histidine, and arginine for babies are obtained through diet.
Amino acid basic structure
The general structure of the standard amino acids includes a primary amino group, a carboxyl group and the functional group attached to the α-carbon. The different amino acids are identified by the functional group. As a result of the three different groups attached to the α-carbon, amino acids are asymmetrical molecules. For all standard amino acids, except glycine, the α-carbon is a chiral center. In the case of glycine, the α-carbon has two hydrogen atoms, thus adding symmetry to this molecule. With the exception of proline, all of the amino acids found in life have the L-isoform conformation. Proline has a functional group on the α-carbon that forms a ring with the amino group.
One major step in amino acid biosynthesis involves incorporating a nitrogen group onto the α-carbon. In cells, there are two major pathways of incorporating nitrogen groups. One pathway involves the enzyme glutamine oxoglutarate aminotransferase (GOGAT) which removes the amide amino group of glutamine and transfers it onto 2-oxoglutarate, resulting with two glutamate molecules. In this catalysis reaction, glutamine serves as the nitrogen source. The other pathway for incorporating nitrogen onto the α-carbon of amino acids involves the enzyme glutamate dehydrogenase (GDH). GDH is able to transfer ammonia onto 2-oxoglutarate and form glutamate. Furthermore, the enzyme glutamine synthetase (GS) is able to transfer ammonia onto glutamate and synthesize glutamine, replenishing glutamine.
Protein synthesis occurs via a process called translation. During translation, genetic material called mRNA is read by ribosomes to generate a protein polypeptide chain. This process requires transfer RNA(tRNA) which serves as an adaptor by binding amino acids on one end and interacting with mRNA at the other end; the latter pairing between the tRNA and mRNA ensures that the correct amino acid is added to the chain. Protein synthesis occurs in three phases: initiation, elongation, and termination. Prokaryotic translation differs from eukaryotic translation; however, this section will mostly focus on the commonalities between the two organisms.
Before translation can begin, the process of binding a specific amino acid to its corresponding tRNA must occur. This reaction, called tRNA charging, is catalyzed by aminoacyl tRNA synthetase. A specific tRNA synthetase is responsible for recognizing and charging a particular amino acid. Furthermore, this enzyme has special discriminator regions to ensure the correct binding between tRNA and its cognate amino acid. The first step for joining an amino acid to its corresponding tRNA is the formation of aminoacyl-AMP:
The combination of these two steps, both of which are catalyzed by aminoacyl tRNA synthetase, produces a charged tRNA that is ready to add amino acids to the growing polypeptide chain.
In addition to binding an amino acid, tRNA has a three nucleotide unit called an anticodon that base pairs with specific nucleotide triplets on the mRNA called codons; codons encode a specific amino acid. This interaction is possible thanks to the ribosome, which serves as the site for protein synthesis. The ribosome possesses three tRNA binding sites: the aminoacyl site (A site), the peptidyl site (P site), and the exit site (E site).
There are numerous codons within an mRNA transcript, and it is very common for an amino acid to be specified by more than one codon; this phenomenon is called degeneracy. In all, there are 64 codons, 61 of each code for one of the 20 amino acids, while the remaining codons specify chain termination.
Translation in steps
As previously mentioned, translation occurs in three phases: initiation, elongation, and termination.
Step 1: Initiation
The completion of the initiation phase is dependent on the following three events:
1. The recruitment of the ribosome to mRNA
2. The binding of a charged initiator tRNA into the P site of the ribosome
3. The proper alignment of the ribosome with mRNA’s start codon
Step 2: Elongation
Following initiation, the polypeptide chain is extended via anticodon:codon interactions, with the ribosome adding amino acids to the polypeptide chain one at a time. The following steps must occur to ensure the correct addition of amino acids:
1. The binding of the correct tRNA into the A site of the ribosome
2. The formation of a peptide bond between the tRNA in the A site and the polypeptide chain attached to the tRNA in the P site
3. Translocation or advancement of the tRNA-mRNA complex by three nucleotides
Translocation “kicks off” the tRNA at the E site and shifts the tRNA from the A site into the P site, leaving the A site free for an incoming tRNA to add another amino acid.
Step 3: Termination
2. The polypeptide chain is released 
3. The ribosome dissociates and is “recycled” for future translation processes 
A summary table of the key players in translation is found below:
|Key players in Translation||Translation Stage||Purpose|
|tRNA synthetase||before initiation||Responsible for tRNA charging|
|mRNA||initiation, elongation, termination||Template for protein synthesis; contains regions named codons which encode amino acids|
|tRNA||initiation, elongation, termination||Binds ribosomes sites A, P, E; anticodon base pairs with mRNA codon to ensure that the correct amino acid is incorporated into the growing polypeptide chain|
|ribosome||initiation, elongation, termination||Directs protein synthesis and catalyzes the formation of the peptide bond|
Diseases associated with macromolecule deficiency
Errors in biosynthesis pathways can have deleterious consequences including the malformation of macromolecules or the underproduction of functional molecules. Below are examples that illustrate the disruptions that occur due to these inefficiencies.
- Familial hypercholesterolemia: this disorder is characterized by the absence of functional receptors for LDL. Deficiencies in the formation of LDL receptors may cause faulty receptors which disrupt the endocytic pathway, inhibiting the entry of LDL into the liver and other cells. This causes a buildup of LDL in the blood plasma, which results in atherosclerotic plaques that narrow arteries and increase the risk of heart attacks.
- Lesch-Nyhan syndrome: this genetic disease is characterized by self- mutilation, mental deficiency, and gout. It is caused by the absence of hypoxanthine-guanine phosphoribosyltransferase, which is a necessary enzyme for purine nucleotide formation. The lack of enzyme reduces the level of necessary nucleotides and causes the accumulation of biosynthesis intermediates, which results in the aforementioned unusual behavior.
- Severe combined immunodeficiency (SCID): SCID is characterized by a loss of T cells. Shortage of these immune system components increases the susceptibility to infectious agents because the affected individuals cannot develop immunological memory. This immunological disorder results from a deficiency in adenosine deanimase activity, which causes a buildup of dATP. These dATP molecules then inhibit ribonucleotide reductase, which prevents of DNA synthesis.
- Huntington’s disease: This neurological disease is caused from errors that occur during DNA synthesis. These errors or mutations lead to the expression of a mutant huntingtin protein, which contains repetitive glutamine residues that are encoded by expanding CAG trinucleotide repeats in the gene. Huntington’s disease is characterized by neuronal loss and gliosis. Symptoms of the disease include: movement disorder and cognitive decline.
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