Biosynthesis

Source: Wikipedia, the free encyclopedia.

In

lipid membrane components and nucleotides. Biosynthesis is usually synonymous with anabolism
.

The prerequisite elements for biosynthesis include:

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:[1]

  • reactants
    in a given chemical process.
  • phosphates
    . Often, the terminal phosphate is split off during hydrolysis and transferred to another molecule.
  • 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:[2]

Some variations of this basic equation which will be discussed later in more detail are:[3]

  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
    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, sphingolipids, requires NADH and FADH for the formation the sphingosine backbone. The general equation for these examples is:
  3. Simple compounds that join to create a macromolecule. For example,
    noncovalently in order to form the lipid bilayer
    . This reaction may be depicted as follows:

Lipid

Lipid membrane bilayer

Many intricate macromolecules are synthesized in a pattern of simple, repeated structures.

carboxyl 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:
sphingolipids. A third major membrane component, cholesterol, does not contain these fatty acid units.[5]

Phospholipids

The foundation of all biomembranes consists of a

hydrophobic 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]

There are various types of phospholipids; consequently, their synthesis pathways differ. However, the first step in phospholipid synthesis involves the formation of

The synthesis pathway is found below:

Phosphatidic acid synthesis
Phosphatidic acid synthesis

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.[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 phosphate acyltransferase enzyme.[9] Phospholipid synthesis continues in the endoplasmic reticulum, and the biosynthesis pathway diverges depending on the components of the particular phospholipid.[9]

Sphingolipids

Like phospholipids, these fatty acid derivatives have a polar head and nonpolar tails.

myelin sheath of nerve fibers.[11]

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.[11] The biosynthetic pathway for sphingosine is found below:

Sphingosine synthesis
Sphingosine synthesis

As the image denotes, during sphingosine synthesis,

oxidation reaction by FAD.[7]

Cholesterol

This

hydroxyl 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 several steroid hormones, including cortisol, testosterone, and estrogen.[12]

Cholesterol is synthesized from

The pathway is shown below:

Cholesterol synthesis pathway
Cholesterol synthesis pathway

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.[9] The stages are as follows:[12]

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

Nucleotides

The biosynthesis of

catalyzed reactions that convert substrates into more complex products.[1] 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.[13]

Purine nucleotides

The synthesis of IMP.

The DNA nucleotides

IMP
produces the adenosine and guanosine bases of nucleotides.

  1. The first step in purine biosynthesis is a
    5-phosphoribosylamine. The following step requires the activation of glycine by the addition of a phosphate group from ATP
    .
  2. GAR synthetase[15] performs the condensation of activated glycine onto PRPP, forming glycineamide ribonucleotide (GAR).
  3. formyl group
    onto the amino group of GAR, forming formylglycinamide ribonucleotide (FGAR).
  4. FGAR amidotransferase[16] catalyzes the addition of a nitrogen group to FGAR, forming formylglycinamidine ribonucleotide (FGAM).
  5. FGAM cyclase catalyzes ring closure, which involves removal of a water molecule, forming the 5-membered imidazole ring 5-aminoimidazole ribonucleotide (AIR).
  6. N5-CAIR synthetase transfers a
    carboxyl group, forming the intermediate N5-carboxyaminoimidazole ribonucleotide (N5-CAIR).[17]
  7. 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,[18]
    which transfers a carboxyl group directly to AIR imidazole ring, forming CAIR.
  8. aspartate and the added carboxyl group of the imidazole ring, forming N-succinyl-5-aminoimidazole-4-carboxamide ribonucleotide
    (SAICAR).
  9. SAICAR lyase removes the carbon skeleton of the added aspartate, leaving the amino group and forming 5-aminoimidazole-4-carboxamide ribonucleotide (AICAR).
  10. AICAR transformylase transfers a carbonyl group to AICAR, forming N-formylaminoimidazole- 4-carboxamide ribonucleotide
    (FAICAR).
  11. The final step involves the enzyme IMP synthase, which performs the purine ring closure and forms the inosine monophosphate intermediate.[5]

Pyrimidine nucleotides

Uridine monophosphate (UMP) biosynthesis

Other DNA and RNA nucleotide bases that 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.[19]

  1. The first step involves the enzyme
    CO2 in an ATP dependent reaction to form carbamoyl phosphate
    .
  2. Aspartate carbamoyltransferase condenses carbamoyl phosphate with aspartate to form uridosuccinate.
  3. dihydroorotate
    .
  4. orotate
    .
  5. Orotate phosphoribosyl hydrolase (OMP pyrophosphorylase) condenses orotate with .
  6. OMP decarboxylase catalyzes the conversion of orotidine-5'-phosphate to UMP.[20]

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

amino 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:

'Thymidylate synthase reaction: dUMP + 5,10-methylenetetrahydrofolate ⇔ dTMP + dihydrofolate
'Thymidylate synthase reaction: dUMP + 5,10-methylenetetrahydrofolate ⇔ dTMP + dihydrofolate
Ctp synthase mechanism: UTP + ATP + glutamine ⇔ CTP + ADP + glutamate
Ctp synthase mechanism: UTP + ATP + glutamine ⇔ CTP + ADP + glutamate

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

nucleotide triphosphates to deoxyribonucleotide 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 enzyme

methyl 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.

DNA

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 between

prokaryotic
DNA synthesis, the following section denotes key characteristics of DNA replication shared by both organisms.

primer with a free 3'OH in which to incorporate nucleotides.[23]

In order for DNA replication to occur, a

single-stranded DNA binding proteins maintain the two single-stranded DNA templates stabilized prior to replication.[13]

DNA synthesis is initiated by the RNA polymerase primase, 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, a

phosphodiester bridge that attaches a new nucleotide and releases pyrophosphate.[9]

Two types of strands are created simultaneously during replication: the

covalently joined by DNA 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]

Amino acids

A protein is a polymer that is composed from

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.[25]

Amino acid basic structure

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.[24]

Glutamine oxoglutarate aminotransferase and glutamine synthetase
Glutamine oxoglutarate aminotransferase and glutamine synthetase

Nitrogen source

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

glutamate
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 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.[26]

The glutamate family of amino acids

The

α-ketoglutarate.[27]

The biosynthesis of glutamate and glutamine is a key step in the nitrogen assimilation discussed above. The enzymes

reactions.

In bacteria, the enzyme

ϒ-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]

In the first step of arginine biosynthesis in bacteria, glutamate is

argininosuccinate convert ornithine to arginine.[29]

The diaminopimelic acid pathway

There are two distinct lysine biosynthetic pathways: the diaminopimelic acid pathway and the

α-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]

  1. Aspartate kinase initiates the diaminopimelic acid pathway by phosphorylating aspartate and producing aspartyl phosphate.
  2. NADPH
    -dependent reduction of aspartyl phosphate to yield aspartate semialdehyde.
  3. 4-hydroxy-tetrahydrodipicolinate synthase adds a pyruvate group to the β-aspartyl-4-semialdehyde, and a water molecule is removed. This causes cyclization
    and gives rise to (2S,4S)-4-hydroxy-2,3,4,5-tetrahydrodipicolinate.
  4. 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.
  5. Tetrahydrodipicolinate acyltransferase catalyzes the acetylation reaction that results in ring opening and yields N-acetyl α-amino-ε-ketopimelate.
  6. N-succinyl-α-amino-ε-ketopimelate-glutamate aminotransaminase catalyzes the transamination reaction that removes the keto group of N-acetyl α-amino-ε-ketopimelate and replaces it with an amino group to yield N-succinyl-L-diaminopimelate.[31]
  7. N-acyldiaminopimelate deacylase catalyzes the deacylation of N-succinyl-L-diaminopimelate to yield L,L-diaminopimelate.[32]
  8. meso form of L,L-diaminopimelate.[33]
  9. DAP decarboxylase catalyzes the removal of the carboxyl group, yielding L-lysine.

The serine family of amino acids

The serine family of amino acid includes: serine, cysteine, and glycine. Most microorganisms and plants obtain the sulfur for synthesizing methionine from the amino acid cysteine. Furthermore, the conversion of serine to glycine provides the carbons needed for the biosynthesis of the methionine and histidine.[27]

During serine biosynthesis,

L-serine.[37]

There are two known pathways for the biosynthesis of glycine. Organisms that use

Cysteine biosynthesis is a two-step reaction that involves the incorporation of inorganic

O-acetyl-L-serine.[39] The following reaction step, catalyzed by the enzyme O-acetyl serine (thiol) lyase, replaces the acetyl group of O-acetyl-L-serine with sulfide to yield cysteine.[40]

The aspartate family of amino acids

The

pyruvate. 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 enzyme

oxaloacetate.[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]

  1. phosphoryl from ATP onto the carboxylate group of aspartate, which yields aspartyl-β-phosphate.[44]
  2. Aspartate-semialdehyde dehydrogenase catalyzes the reduction reaction by dephosphorylation of aspartyl-β-phosphate to yield aspartate-β-semialdehyde.[45]
  3. Dihydrodipicolinate synthase catalyzes the condensation reaction of aspartate-β-semialdehyde with pyruvate to yield dihydrodipicolinic acid.[46]
  4. 4-hydroxy-tetrahydrodipicolinate reductase catalyzes the reduction of dihydrodipicolinic acid to yield tetrahydrodipicolinic acid.[47]
  5. Tetrahydrodipicolinate N-succinyltransferase catalyzes the transfer of a succinyl group from succinyl-CoA on to tetrahydrodipicolinic acid to yield N-succinyl-L-2,6-diaminoheptanedioate.[48]
  6. 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]
  7. Succinyl-diaminopimelate desuccinylase catalyzes the removal of acyl group from N-succinyl-L,L-diaminopimelic acid to yield L,L-diaminopimelic acid.[50]
  8. meso-diaminopimelic acid.[51]
  9. Siaminopimelate decarboxylase catalyzes the final step in lysine biosynthesis that removes the carbon dioxide group from meso-diaminopimelic acid to yield L-lysine.[52]

Proteins

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 called

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.[53] Protein synthesis occurs in three phases: initiation, elongation, and termination.[13] Prokaryotic (archaeal and bacterial) translation differs from eukaryotic translation
; however, this section will mostly focus on the commonalities between the two organisms.

Additional background

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.[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 is aminoacyl-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 an

codons; 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 called degeneracy.[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]

Translation in steps

As previously mentioned, translation occurs in three phases: initiation, elongation, and termination.

Translation

Step 1: Initiation

The completion of the initiation phase is dependent on the following three events:[13]

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:[58]

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

The last stage of translation occurs when a stop codon enters the A site.[1] Then, the following steps occur:

1. The recognition of codons by release factors, which causes the hydrolysis of the polypeptide chain from the tRNA located in the P site[1]

2. The release of the polypeptide chain[57]

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

Diseases associated with macromolecule deficiency

Familial hypercholesterolemia causes cholesterol deposits

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.

  • atherosclerotic plaques that narrow arteries and increase the risk of heart attacks.[59]
  • self- mutilation, mental deficiency, and gout.[60] It is caused by the absence of hypoxanthine-guanine phosphoribosyltransferase, which is a necessary enzyme for purine nucleotide formation.[60] The lack of enzyme reduces the level of necessary nucleotides and causes the accumulation of biosynthesis intermediates, which results in the aforementioned unusual behavior.[60]
  • dATP. These dATP molecules then inhibit ribonucleotide reductase, which prevents of DNA synthesis.[61]
  • cognitive decline, and behavioral disorder.[63]

See also

References

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  34. ^ "Escherichia coli K-12 substr. MG1655". serine biosynthesis. SRI International. Retrieved 12 December 2013.
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