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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 (or previously converted through biosynthesis) serve as enzymesubstrates, with conversion by the living organism either into simpler or more complexproducts. Examples of biosynthetic pathways include those for the production ofamino acids,lipid membrane components, andnucleotides, but also for the production of all classes of biologicalmacromolecules, and ofacetyl-coenzyme A,adenosine triphosphate,nicotinamide adenine dinucleotide and other key intermediate and transactional molecules needed formetabolism. Thus, in biosynthesis, any of an array ofcompounds, from simple to complex, are converted into other compounds, and so it includes both thecatabolism andanabolism (building up and breaking down) of complex molecules (includingmacromolecules). Biosynthetic processes are often represented via charts ofmetabolic pathways. A particular biosynthetic pathway may be located within a single cellularorganelle (e.g.,mitochondrial fatty acid synthesis pathways), while others involve enzymes that are located across an array of cellular organelles and structures (e.g., the biosynthesis of glycosylated cell surface proteins).
Biosynthesis occurs due to a series of chemical reactions. For these reactions to take place, the following elements are necessary:[1]
Precursor compounds: these compounds are the starting molecules orsubstrates in a reaction. These may also be viewed as thereactants 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, thehydrolysis of these compounds drives a reaction forward. High energy molecules, such asATP, have threephosphates. Often, the terminal phosphate is split off during hydrolysis and transferred to another molecule.
In the simplest sense, the reactions that occur in biosynthesis have the following format:[2]
Some variations of this basic equation which will be discussed later in more detail are:[3]
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 ofnucleic acids and thecharging oftRNA prior totranslation. For some of these steps, chemical energy is required:
Simple compounds that are converted into other compounds with the assistance of cofactors. For example, the synthesis ofphospholipids requires acetyl CoA, while the synthesis of another membrane component,sphingolipids, requires NADH and FADH for the formation thesphingosine backbone. The general equation for these examples is:
Simple compounds that join to create a macromolecule. For example,fatty acids join to form phospholipids. In turn, phospholipids andcholesterol interactnoncovalently in order to form thelipid bilayer. This reaction may be depicted as follows:
Many intricate macromolecules are synthesized in a pattern of simple, repeated structures.[4] For example, the simplest structures of lipids arefatty acids. Fatty acids arehydrocarbon derivatives; they contain acarboxyl group "head" and a hydrocarbon chain "tail".[4] These fatty acids create larger components, which in turn incorporate noncovalent interactions to form the lipid bilayer.[4]Fatty acid chains are found in two major components of membrane lipids:phospholipids andsphingolipids. A third major membrane component,cholesterol, does not contain these fatty acid units.[5]
The foundation of allbiomembranes consists of abilayer structure of phospholipids.[6] The phospholipid molecule isamphipathic; it contains ahydrophilic polar head and ahydrophobic nonpolar tail.[4] The phospholipid heads interact with each other and aqueous media, while the hydrocarbon tails orient themselves in the center, away from water.[7] These latter interactions drive the bilayer structure that acts as a barrier for ions and molecules.[8]
The pathway starts with glycerol 3-phosphate, which gets converted tolysophosphatidate via the addition of a fatty acid chain provided byacyl coenzyme A.[9] 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 phosphateacyltransferase enzyme.[9] Phospholipid synthesis continues in the endoplasmic reticulum, and the biosynthesis pathway diverges depending on the components of the particular phospholipid.[9]
Like phospholipids, these fatty acid derivatives have a polar head and nonpolar tails.[5] Unlike phospholipids, sphingolipids have asphingosine backbone.[10] Sphingolipids exist ineukaryotic cells and are particularly abundant in thecentral nervous system.[7] For example,sphingomyelin is part of themyelin sheath of nerve fibers.[11]
Sphingolipids are formed fromceramides that consist of a fatty acid chain attached to the amino group of a sphingosine backbone. These ceramides are synthesized from theacylation of sphingosine.[11] The biosynthetic pathway for sphingosine is found below:
Sphingosine synthesis
As the image denotes, during sphingosine synthesis,palmitoyl CoA andserine undergo acondensation reaction which results in the formation of 3-dehydrosphinganine.[7] This product is then reduced to form dihydrospingosine, which is converted to sphingosine via theoxidation reaction byFAD.[7]
Thislipid belongs to a class of molecules calledsterols.[5] Sterols have four fused rings and ahydroxyl group.[5] Cholesterol is a particularly important molecule. Not only does it serve as a component of lipid membranes, it is also a precursor to severalsteroid hormones, includingcortisol,testosterone, andestrogen.[12]
Cholesterol is synthesized fromacetyl CoA.[12] The pathway is shown below:
Cholesterol synthesis pathway
More generally, this synthesis occurs in three stages, with the first stage taking place in thecytoplasm and the second and third stages occurring in the endoplasmic reticulum.[9] The stages are as follows:[12]
The biosynthesis ofnucleotides involves enzyme-catalyzed reactions that convert substrates into more complex products.[1] Nucleotides are the building blocks ofDNA andRNA. Nucleotides are composed of a five-membered ring formed fromribose sugar in RNA, anddeoxyribose sugar in DNA; these sugars are linked to apurine orpyrimidine base with aglycosidic bond and aphosphate group at the5' location of the sugar.[13]
The DNA nucleotidesadenosine andguanosine consist of a purine base attached to a ribose sugar with a glycosidic bond. In the case of RNA nucleotidesdeoxyadenosine anddeoxyguanosine, 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. Highereukaryotes employ a similarreaction mechanism in ten reaction steps. Purine bases are synthesized by convertingphosphoribosyl pyrophosphate (PRPP) toinosine monophosphate (IMP), which is the first key intermediate in purine base biosynthesis.[14] Further enzymatic modification ofIMP produces the adenosine and guanosine bases of nucleotides.
N5-CAIR mutase rearranges the carboxyl functional group and transfers it onto the imidazole ring, formingcarboxyamino- 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,[18] which transfers a carboxyl group directly to AIR imidazole ring, forming CAIR.
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 toUTP.Phosphate addition to UMP is catalyzed by akinase enzyme. The enzymeCTP synthase catalyzes the next reaction step: the conversion of UTP toCTP by transferring anamino group from glutamine to uridine; this forms the cytosine base of CTP.[21] 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 must be converted into adeoxy form to be incorporated into DNA. This conversion involves the enzymeribonucleoside 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 allnucleotide triphosphates todeoxyribonucleotide by a similar mechanism.[21]
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, thus indicating that cells only synthesize deoxyribose-linked thymine. The enzymethymidylate synthetase is responsible for synthesizing thymine residues fromdUMP todTMP. This reaction transfers amethyl group onto the uracil base of dUMP to generate dTMP.[21] The thymidylate synthase reaction, dUMP + 5,10-methylenetetrahydrofolate ⇔ dTMP + dihydrofolate, is shown to the right.
As DNA polymerase moves in a 3' to 5' direction along the template strand, it synthesizes a new strand in the 5' to 3' direction
Although there are differences betweeneukaryotic andprokaryotic DNA synthesis, the following section denotes key characteristics of DNA replication shared by both organisms.
DNA synthesis is initiated by theRNA polymeraseprimase, which makes an RNA primer with a free 3'OH.[23] 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.[23]
During the polymerization reaction catalyzed by DNA polymerase, anucleophilic attack occurs by the 3'OH of the growing chain on the innermost phosphorus atom of a deoxynucleoside triphosphate; this yields the formation of aphosphodiester bridge that attaches a new nucleotide and releasespyrophosphate.[9]
Two types of strands are created simultaneously during replication: theleading strand, which is synthesized continuously and grows towards the replication fork, and thelagging strand, which is made discontinuously inOkazaki fragments and grows away from the replication fork.[22] Okazaki fragments arecovalently joined byDNA ligase to form a continuous strand.[22]Then, to complete DNA replication, RNA primers are removed, and the resulting gaps are replaced with DNA and joined via DNA ligase.[22]
The general structure of the standard amino acids includes aprimary amino group, acarboxyl group and thefunctional group attached to theα-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 areasymmetrical molecules. For all standard amino acids, exceptglycine, the α-carbon is achiral center. In the case of glycine, the α-carbon has two hydrogen atoms, thus adding symmetry to this molecule. With the exception ofproline, all of the amino acids found in life have theL-isoform conformation. Proline has a functional group on the α-carbon that forms a ring with the amino group.[24]
Glutamine oxoglutarate aminotransferase and glutamine synthetase
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 enzymeglutamine oxoglutarate aminotransferase (GOGAT) which removes theamide amino group ofglutamine and transfers it onto2-oxoglutarate, producing twoglutamate molecules. In this catalysis reaction, glutamine serves as the nitrogen source. An image illustrating this reaction is found to the right.
The other pathway for incorporating nitrogen onto the α-carbon of amino acids involves the enzymeglutamate dehydrogenase (GDH). GDH is able to transferammonia onto 2-oxoglutarate and form glutamate. Furthermore, the enzymeglutamine synthetase (GS) is able to transfer ammonia onto glutamate and synthesize glutamine, replenishing glutamine.[26]
Theglutamate family of amino acids includes the amino acids that derive from the amino acid glutamate. This family includes: glutamate,glutamine,proline, andarginine. This family also includes the amino acidlysine, which is derived fromα-ketoglutarate.[27]
The biosynthesis of glutamate and glutamine is a key step in the nitrogen assimilation discussed above. The enzymesGOGAT andGDH catalyze thenitrogen assimilation reactions.
In bacteria, the enzymeglutamate 5-kinase initiates the biosynthesis of proline by transferring a phosphate group from ATP onto glutamate. The next reaction is catalyzed by the enzymepyrroline-5-carboxylate synthase (P5CS), which catalyzes the reduction of theϒ-carboxyl group of L-glutamate 5-phosphate. This results in the formation of glutamate semialdehyde, which spontaneously cyclizes to pyrroline-5-carboxylate. Pyrroline-5-carboxylate is further reduced by the enzyme pyrroline-5-carboxylate reductase (P5CR) to yield a proline amino acid.[28]
There are two distinct lysine biosynthetic pathways: the diaminopimelic acid pathway and theα-aminoadipate pathway. The most common of the two synthetic pathways is the diaminopimelic acid pathway; it consists of several enzymatic reactions that add carbon groups to aspartate to yield lysine:[30]
Aspartate kinase initiates the diaminopimelic acid pathway by phosphorylating aspartate and producing aspartyl phosphate.
4-hydroxy-tetrahydrodipicolinate reductase catalyzes the reduction of (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate by NADPH to yield Δ'-piperideine-2,6-dicarboxylate (2,3,4,5-tetrahydrodipicolinate) and H2O.
Theserine family of amino acid includes: serine,cysteine, andglycine. Most microorganisms and plants obtain the sulfur for synthesizingmethionine from the amino acid cysteine. Furthermore, the conversion of serine to glycine provides the carbons needed for the biosynthesis of the methionine andhistidine.[27]
There are two known pathways for the biosynthesis of glycine. Organisms that useethanol andacetate as the major carbon source utilize theglyconeogenic pathway to synthesizeglycine. The other pathway of glycine biosynthesis is known as theglycolytic pathway. This pathway converts serine synthesized from the intermediates ofglycolysis to glycine. In the glycolytic pathway, the enzymeserine hydroxymethyltransferase catalyzes the cleavage of serine to yield glycine and transfers the cleaved carbon group of serine ontotetrahydrofolate, forming5,10-methylene-tetrahydrofolate.[38]
Cysteine biosynthesis is a two-step reaction that involves the incorporation of inorganicsulfur. In microorganisms and plants, the enzymeserine acetyltransferase catalyzes the transfer of acetyl group fromacetyl-CoA onto L-serine to yieldO-acetyl-L-serine.[39] The following reaction step, catalyzed by the enzymeO-acetyl serine (thiol) lyase, replaces the acetyl group of O-acetyl-L-serine with sulfide to yield cysteine.[40]
Theaspartate family of amino acids includes:threonine,lysine,methionine,isoleucine, and aspartate. Lysine and isoleucine are considered part of the aspartate family even though part of their carbon skeleton is derived frompyruvate. In the case of methionine, the methyl carbon is derived from serine and the sulfur group, but in most organisms, it is derived from cysteine.[27]
The biosynthesis of aspartate is a one step reaction that is catalyzed by a single enzyme. The enzymeaspartate aminotransferase catalyzes the transfer of an amino group from aspartate ontoα-ketoglutarate to yield glutamate andoxaloacetate.[41] Asparagine is synthesized by an ATP-dependent addition of an amino group onto aspartate;asparagine synthetase catalyzes the addition of nitrogen from glutamine or soluble ammonia to aspartate to yield asparagine.[42]
The diaminopimelic acid lysine biosynthetic pathway
The diaminopimelic acid biosynthetic pathway of lysine belongs to the aspartate family of amino acids. This pathway involves nine enzyme-catalyzed reactions that convert aspartate to lysine.[43]
Aspartate kinase catalyzes the initial step in the diaminopimelic acid pathway by transferring aphosphoryl from ATP onto the carboxylate group of aspartate, which yields aspartyl-β-phosphate.[44]
N-succinyldiaminopimelate aminotransferase catalyzes the transfer of an amino group from glutamate onto N-succinyl-L-2,6-diaminoheptanedioate to yield N-succinyl-L,L-diaminopimelic acid.[49]
Siaminopimelate decarboxylase catalyzes the final step in lysine biosynthesis that removes the carbon dioxide group from meso-diaminopimelic acid to yield L-lysine.[52]
The tRNA anticodon interacts with the mRNA codon in order to bind an amino acid to growing polypeptide chain.The process of tRNA charging
Protein synthesis occurs via a process calledtranslation.[53] During translation, genetic material calledmRNA is read byribosomes to generate a proteinpolypeptide chain.[53] This process requirestransfer RNA (tRNA) which serves as an adaptor by bindingamino 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.[53] Protein synthesis occurs in three phases: initiation, elongation, and termination.[13] Prokaryotic (archaeal andbacterial) translation differs fromeukaryotic 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 byaminoacyl tRNA synthetase.[54] A specific tRNA synthetase is responsible for recognizing and charging a particular amino acid.[54] Furthermore, this enzyme has special discriminator regions to ensure the correct binding between tRNA and its cognate amino acid.[54] The first step for joining an amino acid to its corresponding tRNA is the formation of aminoacyl-AMP:[54]
This is followed by the transfer of the aminoacyl group from aminoacyl-AMP to a tRNA molecule. The resulting molecule isaminoacyl-tRNA:[54]
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 ananticodon thatbase pairs with specific nucleotide triplets on the mRNA calledcodons; codons encode a specific amino acid.[55] 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).[56]
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 calleddegeneracy.[57] In all, there are 64 codons, 61 of each code for one of the 20 amino acids, while the remaining codons specify chain termination.[57]
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:[58]
1.The binding of the correct tRNA into the A site of the ribosome
2.The formation of apeptide 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.
3.The dissociation and "recycling" of the ribosome for future translation processes[57]
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
Errors in biosynthetic 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 functionalreceptors forLDL.[59] Deficiencies in the formation of LDL receptors may cause faulty receptors which disrupt theendocytic pathway, inhibiting the entry of LDL into the liver and other cells.[59] This causes a buildup of LDL in the blood plasma, which results inatherosclerotic plaques that narrow arteries and increase the risk of heart attacks.[59]
Severe combined immunodeficiency (SCID): SCID is characterized by a loss ofT cells.[61] Shortage of these immune system components increases the susceptibility to infectious agents because the affected individuals cannot developimmunological memory.[61] This immunological disorder results from a deficiency inadenosine deaminase activity, which causes a buildup ofdATP. These dATP molecules then inhibit ribonucleotide reductase, which prevents of DNA synthesis.[61]
Huntington's disease: thisneurological disease is caused from errors that occur during DNA synthesis.[62] These errors or mutations lead to the expression of a mutanthuntingtin protein, which contains repetitiveglutamine residues that are encoded by expandingCAG trinucleotide repeats in the gene.[62] Huntington's disease is characterized by neuronal loss andgliosis. Symptoms of the disease include: movement disorder,cognitive decline, and behavioral disorder.[63]
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