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74-491: This enzyme participates in the pentose phosphate pathway (see image), a metabolic pathway that supplies reducing energy to cells (such as erythrocytes ) by maintaining the level of the reduced form of the co-enzyme nicotinamide adenine dinucleotide phosphate (NADPH). The NADPH in turn maintains the level of glutathione in these cells that helps protect the red blood cells against oxidative damage from compounds like hydrogen peroxide . Of greater quantitative importance

148-688: A catalytic coenzyme binding site that binds to NADP/NADPH using the Rossman fold . For some higher organisms, such as humans, G6PD contains an additional NADP binding site, called the NADP structural site, that does not seem to participate directly in the reaction catalyzed by G6PD. The evolutionary purpose of the NADP structural site is unknown. As for size, each monomer is approximately 500 amino acids long (514 amino acids for humans). Functional and structural conservation between human G6PD and Leuconostoc mesenteroides G6PD points to 3 widely conserved regions on

222-539: A general base in catalysis . The ε- ammonium group ( −NH + 3 ) is attached to the fourth carbon from the α-carbon, which is attached to the carboxyl ( −COOH ) group. Due to its importance in several biological processes, a lack of lysine can lead to several disease states including defective connective tissues, impaired fatty acid metabolism, anaemia, and systemic protein-energy deficiency. In contrast, an overabundance of lysine, caused by ineffective catabolism, can cause severe neurological disorders . Lysine

296-798: A human prone to non-immune hemolytic anemia . G6PD is widely distributed in many species from bacteria to humans . Multiple sequence alignment of over 100 known G6PDs from different organisms reveal sequence identity ranging from 30% to 94%. Human G6PD has over 30% identity in amino acid sequence to G6PD sequences from other species. Humans also have two isoforms of a single gene coding for G6PD. Moreover, at least 168 disease-causing mutations in this gene have been discovered. These mutations are mainly missense mutations that result in amino acid substitutions, and while some of them result in G6PD deficiency, others do not seem to result in any noticeable functional differences. Some scientists have proposed that some of

370-745: A lack of lysine catabolism, the amino acid accumulates in plasma and patients develop hyperlysinaemia , which can present as asymptomatic to severe neurological disabilities , including epilepsy , ataxia , spasticity , and psychomotor impairment . The clinical significance of hyperlysinemia is the subject of debate in the field with some studies finding no correlation between physical or mental disabilities and hyperlysinemia. In addition to this, mutations in genes related to lysine metabolism have been implicated in several disease states, including pyridoxine-dependent epilepsia ( ALDH7A1 gene ), α-ketoadipic and α-aminoadipic aciduria ( DHTKD1 gene ), and glutaric aciduria type 1 ( GCDH gene ). Hyperlysinuria

444-421: A long discussion that lysine, when administered intravenously or orally, can significantly increase the release of growth hormones . This has led to athletes using lysine as a means of promoting muscle growth while training, however, no significant evidence to support this application of lysine has been found to date. Because herpes simplex virus (HSV) proteins are richer in arginine and poorer in lysine than

518-410: A precursor for carnitine , which transports fatty acids to the mitochondria , where they can be oxidised for the release of energy. Carnitine is synthesised from trimethyllysine , which is a product of the degradation of certain proteins, as such lysine must first be incorporated into proteins and be methylated prior to being converted to carnitine. However, in mammals the primary source of carnitine

592-412: A precursor for the synthesis of nucleotides . While the pentose phosphate pathway does involve oxidation of glucose , its primary role is anabolic rather than catabolic . The pathway is especially important in red blood cells (erythrocytes). The reactions of the pathway were elucidated in the early 1950s by Bernard Horecker and co-workers. There are two distinct phases in the pathway. The first

666-435: A proton donor, to yield 2,3,4,5-tetrahydrodipicolinate (THDP). From this point on, four pathway variations have been found, namely the acetylase, aminotransferase, dehydrogenase, and succinylase pathways. Both the acetylase and succinylase variant pathways use four enzyme catalysed steps, the aminotransferase pathway uses two enzymes, and the dehydrogenase pathway uses a single enzyme. These four variant pathways converge at

740-429: A result of the downstream processing of lysine, i.e. the incorporation into proteins or modification into alternative biomolecules. The role of lysine in collagen has been outlined above, however, a lack of lysine and hydroxylysine involved in the crosslinking of collagen peptides has been linked to a disease state of the connective tissue. As carnitine is a key lysine-derived metabolite involved in fatty acid metabolism,

814-414: A strong negative feedback loop on these enzymes and, subsequently, regulates the entire pathway. The AAA pathway involves the condensation of α-ketoglutarate and acetyl-CoA via the intermediate AAA for the synthesis of L -lysine. This pathway has been shown to be present in several yeast species, as well as protists and higher fungi. It has also been reported that an alternative variant of

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888-403: A substandard diet lacking sufficient carnitine and lysine can lead to decreased carnitine levels, which can have significant cascading effects on an individual's health. Lysine has also been shown to play a role in anaemia , as lysine is suspected to have an effect on the uptake of iron and, subsequently, the concentration of ferritin in blood plasma . However, the exact mechanism of action

962-421: A variant AAA pathway found in some prokaryotes, AAA is first converted to N ‑acetyl-α-aminoadipate, which is phosphorylated and then reductively dephosphorylated to the ε-aldehyde. The aldehyde is then transaminated to N ‑acetyllysine, which is deacetylated to give L -lysine. However, the enzymes involved in this variant pathway need further validation. As with all amino acids, catabolism of lysine

1036-444: Is hydrolysed by the same enzyme to produce homocitrate . Homocitrate is enzymatically dehydrated by homoaconitase (HAc) (E.C 4.2.1.36) to yield cis -homoaconitate . HAc then catalyses a second reaction in which cis -homoaconitate undergoes rehydration to produce homoisocitrate . The resulting product undergoes an oxidative decarboxylation by homoisocitrate dehydrogenase (HIDH) (E.C 1.1.1.87) to yield α‑ketoadipate. AAA

1110-406: Is a precursor to many proteins . Lysine contains an α-amino group (which is in the protonated −NH + 3 form when the lysine is dissolved in water at physiological pH ), an α-carboxylic acid group (which is in the deprotonated −COO form when the lysine is dissolved in water at physiological pH), and a side chain (CH 2 ) 4 NH 2 (which is partially protonated when the lysine

1184-555: Is a major environmental cost when corn is used as feed for poultry and swine. Lysine is industrially produced by microbial fermentation, from a base mainly of sugar. Genetic engineering research is actively pursuing bacterial strains to improve the efficiency of production and allow lysine to be made from other substrates. The most common bacteria used is Corynebacterium glutamicum specially mutagenized or gene-engineered to produce lysine, but analogous strains of Escherichia coli are also employed. The 1993 film Jurassic Park , which

1258-461: Is a strong network of hydrogen bonding with electrostatic charges being diffused across multiple atoms through hydrogen bonding with 4 water molecules (see figure). Moreover, there is an extremely strong set of hydrophobic stacking interactions that result in overlapping π systems. The structural site has been shown to be important for maintaining the long term stability of the enzyme. More than 40 severe class I mutations involve mutations near

1332-484: Is activated by a phosphopantetheinyl transferase (E.C 2.7.8.7). Once the semialdehyde is formed, saccharopine reductase (E.C 1.5.1.10) catalyses a condensation reaction with glutamate and NAD(P)H, as a proton donor, and the imine is reduced to produce the penultimate product, saccharopine. The final step of the pathway in fungi involves the saccharopine dehydrogenase (SDH) (E.C 1.5.1.8) catalysed oxidative deamination of saccharopine, resulting in L -lysine. In

1406-469: Is also inhibited by acetyl CoA . G6PD activity is also post-translationally regulated by cytoplasmic deacetylase SIRT2 . SIRT2-mediated deacetylation and activation of G6PD stimulates oxidative branch of PPP to supply cytosolic NADPH to counteract oxidative damage or support de novo lipogenesis . Several deficiencies in the level of activity (not function) of glucose-6-phosphate dehydrogenase have been observed to be associated with resistance to

1480-487: Is an essential amino acid . In 1996, lysine became the focus of a price-fixing case , the largest in United States history. The Archer Daniels Midland Company paid a fine of US$ 100 million, and three of its executives were convicted and served prison time. Also found guilty in the price-fixing case were two Japanese firms ( Ajinomoto , Kyowa Hakko) and a South Korean firm (Sewon). Secret video recordings of

1554-414: Is an important additive to animal feed because it is a limiting amino acid when optimizing the growth of certain animals such as pigs and chickens for the production of meat. Lysine supplementation allows for the use of lower-cost plant protein (maize, for instance, rather than soy ) while maintaining high growth rates, and limiting the pollution from nitrogen excretion. In turn, however, phosphate pollution

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1628-430: Is attributed to an opaque-2 mutation that reduced the transcription of lysine-lacking zein -related seed storage proteins and, as a result, increased the abundance of other proteins that are rich in lysine. Commonly, to overcome the limiting abundance of lysine in livestock feed, industrially produced lysine is added. The industrial process includes the fermentative culturing of Corynebacterium glutamicum and

1702-457: Is based on the 1990 novel Jurassic Park by Michael Crichton , features dinosaurs that were genetically altered so that they could not produce lysine, an example of engineered auxotrophy . This was known as the "lysine contingency" and was supposed to prevent the cloned dinosaurs from surviving outside the park, forcing them to depend on lysine supplements provided by the park's veterinary staff. In reality, no animal can produce lysine; it

1776-493: Is commonly met in a western society with the intake of lysine from meat and vegetable sources well in excess of the recommended requirement. In vegetarian diets, the intake of lysine is less due to the limited quantity of lysine in cereal crops compared to meat sources. Given the limiting concentration of lysine in cereal crops, it has long been speculated that the content of lysine can be increased through genetic modification practices. Often these practices have involved

1850-437: Is contained in 1.25 g of L -lysine HCl. The most common role for lysine is proteinogenesis. Lysine frequently plays an important role in protein structure . Since its side chain contains a positively charged group on one end and a long hydrophobic carbon tail close to the backbone, lysine is considered somewhat amphipathic . For this reason, lysine can be found buried as well as more commonly in solvent channels and on

1924-433: Is dissolved in water at physiological pH), and so it is classified as a basic , charged (in water at physiological pH), aliphatic amino acid. It is encoded by the codons AAA and AAG. Like almost all other amino acids, the α-carbon is chiral and lysine may refer to either enantiomer or a racemic mixture of both. For the purpose of this article, lysine will refer to the biologically active enantiomer L -lysine, where

1998-414: Is found in both prokaryotes and plants and begins with the dihydrodipicolinate synthase (DHDPS) (E.C 4.3.3.7) catalysed condensation reaction between the aspartate derived, L -aspartate semialdehyde, and pyruvate to form (4 S )-4-hydroxy-2,3,4,5-tetrahydro-(2 S )-dipicolinic acid (HTPA). The product is then reduced by dihydrodipicolinate reductase (DHDPR) (E.C 1.3.1.26), with NAD(P)H as

2072-592: Is incapable of forming active dimers and displays a complete loss of activity. Mechanistically, acetylating Lys403 sterically hinders the NADP from entering the NADP structural site, which reduces the stability of the enzyme. Cells sense extracellular oxidative stimuli to decrease G6PD acetylation in a SIRT2 -dependent manner. The SIRT2-mediated deacetylation and activation of G6PD stimulates pentose phosphate pathway to supply cytosolic NADPH to counteract oxidative damage and protect mouse erythrocytes . Regulation can also occur through genetic pathways. The isoform, G6PDH,

2146-419: Is initiated from the uptake of dietary lysine or from the breakdown of intracellular protein. Catabolism is also used as a means to control the intracellular concentration of free lysine and maintain a steady-state to prevent the toxic effects of excessive free lysine. There are several pathways involved in lysine catabolism but the most commonly used is the saccharopine pathway, which primarily takes place in

2220-418: Is marked by high amounts of lysine in the urine. It is often due to a metabolic disease in which a protein involved in the breakdown of lysine is non functional due to a genetic mutation. It may also occur due to a failure of renal tubular transport. Lysine production for animal feed is a major global industry, reaching in 2009 almost 700,000 tons for a market value of over €1.22 billion. Lysine

2294-496: Is of interest for treating tuberculosis . The bacterial G6PD found in Leuconostoc mesenteroides was shown to be reactive toward 4-hydroxynonenal , in addition to G6P. G6PD is generally found as a dimer of two identical monomers (see main thumbnail). Depending on conditions, such as pH , these dimers can themselves dimerize to form tetramers . Each monomer in the complex has a substrate binding site that binds to G6P, and

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2368-545: Is plentiful in most pulses (legumes). Beans contain the lysine that maize lacks, and in the human archeological record beans and maize often appear together, as in the Three Sisters : beans, maize, and squash. A food is considered to have sufficient lysine if it has at least 51 mg of lysine per gram of protein (so that the protein is 5.1% lysine). L -lysine HCl is used as a dietary supplement , providing 80.03% L -lysine. As such, 1 g of L -lysine

2442-544: Is regulated by transcription and posttranscription factors. Moreover, G6PD is one of a number of glycolytic enzymes activated by the transcription factor hypoxia-inducible factor 1 (HIF1). G6PD is remarkable for its genetic diversity. Many variants of G6PD, mostly produced from missense mutations , have been described with wide-ranging levels of enzyme activity and associated clinical symptoms . Two transcript variants encoding different isoforms have been found for this gene. Glucose-6-phosphate dehydrogenase deficiency

2516-517: Is responsible for the decarboxylation reaction. Finally, glutaryl-CoA is oxidatively decarboxylated to crotonyl-CoA by glutaryl-CoA dehydrogenase (E.C 1.3.8.6), which goes on to be further processed through multiple enzymatic steps to yield acetyl-CoA; an essential carbon metabolite involved in the tricarboxylic acid cycle (TCA) . Lysine is an essential amino acid in humans. The human daily nutritional requirement varies from ~60 mg/kg in infancy to ~30 mg/kg in adults. This requirement

2590-516: Is the oxidative phase, in which NADPH is generated, and the second is the non-oxidative synthesis of five-carbon sugars. For most organisms, the pentose phosphate pathway takes place in the cytosol ; in plants, most steps take place in plastids . Like glycolysis , the pentose phosphate pathway appears to have a very ancient evolutionary origin. The reactions of this pathway are mostly enzyme catalyzed in modern cells, however, they also occur non-enzymatically under conditions that replicate those of

2664-473: Is the production of NADPH for tissues involved in biosynthesis of fatty acids or isoprenoids , such as the liver, mammary glands , adipose tissue , and the adrenal glands . G6PD reduces NADP to NADPH while oxidizing glucose-6-phosphate . Glucose-6-phosphate dehydrogenase is also an enzyme in the Entner–Doudoroff pathway , a type of glycolysis. Clinically, an X-linked genetic deficiency of G6PD makes

2738-429: Is the rate-controlling enzyme of this pathway . It is allosterically stimulated by NADP and strongly inhibited by NADPH . The ratio of NADPH:NADP is the primary mode of regulation for the enzyme and is normally about 100:1 in liver cytosol . This makes the cytosol a highly-reducing environment. An NADPH-utilizing pathway forms NADP , which stimulates Glucose-6-phosphate dehydrogenase to produce more NADPH. This step

2812-491: Is then formed via a pyridoxal 5′-phosphate (PLP) -dependent aminotransferase (PLP-AT) (E.C 2.6.1.39), using glutamate as the amino donor. From this point on, the AAA pathway varies with [something is missing here ? -> at the very least, section header! ] on the kingdom. In fungi, AAA is reduced to α‑aminoadipate-semialdehyde via AAA reductase (E.C 1.2.1.95) in a unique process involving both adenylation and reduction that

2886-426: Is thought to play a crucial role in positioning Lys171 correctly with respect to the substrate, G6P. In the two crystal structures of normal human G6P, Pro172 is seen exclusively in the cis conformation , while in the crystal structure of one disease causing mutant (variant Canton R459L), Pro172 is seen almost exclusively in the trans conformation. With access to crystal structures, some scientists have tried to model

2960-399: Is through dietary sources, rather than through lysine conversion. In opsins like rhodopsin and the visual opsins (encoded by the genes OPN1SW , OPN1MW , and OPN1LW ), retinaldehyde forms a Schiff base with a conserved lysine residue, and interaction of light with the retinylidene group causes signal transduction in color vision (See visual cycle for details). There has been

3034-611: Is very common worldwide, and causes acute hemolytic anemia in the presence of simple infection, ingestion of fava beans , or reaction with certain medicines, antibiotics, antipyretics, and antimalarials. Cell growth and proliferation are affected by G6PD. Pharmacologically ablating G6PD has been shown to overcome cross-tolerance of breast cancer cells to anthracyclines. G6PD inhibitors are under investigation to treat cancers and other conditions. In vitro cell proliferation assay indicates that G6PD inhibitors, DHEA (dehydroepiandrosterone) and ANAD (6-aminonicotinamide), effectively decrease

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3108-408: Is yet to be elucidated. Most commonly, lysine deficiency is seen in non-western societies and manifests as protein-energy malnutrition , which has profound and systemic effects on the health of the individual. There is also a hereditary genetic disease that involves mutations in the enzymes responsible for lysine catabolism, namely the bifunctional AASS enzyme of the saccharopine pathway. Due to

3182-485: The Archean ocean, and are catalyzed by metal ions , particularly ferrous ions (Fe(II)). This suggests that the origins of the pathway could date back to the prebiotic world. The primary results of the pathway are: Aromatic amino acids, in turn, are precursors for many biosynthetic pathways, including the lignin in wood. Dietary pentose sugars derived from the digestion of nucleic acids may be metabolized through

3256-481: The crosslinking between the three helical polypeptides in collagen , resulting in its stability and tensile strength. This mechanism is akin to the role of lysine in bacterial cell walls , in which lysine (and meso -diaminopimelate) are critical to the formation of crosslinks, and therefore, stability of the cell wall. This concept has previously been explored as a means to circumvent the unwanted release of potentially pathogenic genetically modified bacteria. It

3330-482: The genetic variation in human G6PD resulted from generations of adaptation to malarial infection. Other species experience a variation in G6PD as well. In higher plants, several isoforms of G6PDH have been reported, which are localized in the cytosol , the plastidic stroma , and peroxisomes . A modified F 420 -dependent (as opposed to NADP-dependent) G6PD is found in Mycobacterium tuberculosis , and

3404-540: The liver (and equivalent organs) in animals, specifically within the mitochondria . This is the reverse of the previously described AAA pathway. In animals and plants, the first two steps of the saccharopine pathway are catalysed by the bifunctional enzyme, α-aminoadipic semialdehyde synthase (AASS) , which possess both lysine-ketoglutarate reductase (LKR) (E.C 1.5.1.8) and SDH activities, whereas in other organisms, such as bacteria and fungi, both of these enzymes are encoded by separate genes . The first step involves

3478-499: The AAA biosynthesis pathway, resulting in AAA being converted to α-ketoadipate. The product, α‑ketoadipate, is decarboxylated in the presence of NAD and coenzyme A to yield glutaryl-CoA, however the enzyme involved in this is yet to be fully elucidated. Some evidence suggests that the 2-oxoadipate dehydrogenase complex (OADHc), which is structurally homologous to the E1 subunit of the oxoglutarate dehydrogenase complex (OGDHc) (E.C 1.2.4.2),

3552-471: The AAA route has been found in Thermus thermophilus and Pyrococcus horikoshii , which could indicate that this pathway is more widely spread in prokaryotes than originally proposed. The first and rate-limiting step in the AAA pathway is the condensation reaction between acetyl-CoA and α‑ketoglutarate catalysed by homocitrate-synthase (HCS) (E.C 2.3.3.14) to give the intermediate homocitryl‑CoA, which

3626-472: The LKR catalysed reduction of L -lysine in the presence of α-ketoglutarate to produce saccharopine, with NAD(P)H acting as a proton donor. Saccharopine then undergoes a dehydration reaction, catalysed by SDH in the presence of NAD , to produce AAS and glutamate. AAS dehydrogenase (AASD) (E.C 1.2.1.31) then further dehydrates the molecule into AAA. Subsequently, PLP-AT catalyses the reverse reaction to that of

3700-412: The NADP structural site. The NADP structural site is located greater than 20Å away from the substrate binding site and the catalytic coenzyme NADP binding site. Its purpose in the enzyme catalyzed reaction has been unclear for many years. For some time, it was thought that NADP binding to the structural site was necessary for dimerization of the enzyme monomers. However, this was shown to be incorrect. On

3774-409: The cells they infect, lysine supplements have been tried as a treatment. Since the two amino acids are taken up in the intestine, reclaimed in the kidney, and moved into cells by the same amino acid transporters , an abundance of lysine would, in theory, limit the amount of arginine available for viral replication. Clinical studies do not provide good evidence for effectiveness as a prophylactic or in

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3848-510: The cytosol of tissues engaged in biosyntheses is about 100/1. Increased utilization of NADPH for fatty acid biosynthesis will dramatically increase the level of NADP, thus stimulating G6PD to produce more NADPH. Yeast G6PD is inhibited by long chain fatty acids according to two older publications and might be product inhibition in fatty acid synthesis which requires NADPH. G6PD is negatively regulated by acetylation on lysine 403 (Lys403), an evolutionarily conserved residue. The K403 acetylated G6PD

3922-620: The edible component of cereal crops. This highlights the need to not only increase free lysine, but also direct lysine towards the synthesis of stable seed storage proteins, and subsequently, increase the nutritional value of the consumable component of crops. While genetic modification practices have met limited success, more traditional selective breeding techniques have allowed for the isolation of " Quality Protein Maize ", which has significantly increased levels of lysine and tryptophan , also an essential amino acid. This increase in lysine content

3996-610: The enzyme: a 9 residue peptide in the substrate binding site, RIDHYLGKE (residues 198-206 on human G6PD), a nucleotide-binding fingerprint, GxxGDLA (residues 38-44 on human G6PD), and a partially conserved sequence EKPxG near the substrate binding site (residues 170-174 on human G6PD), where we have use "x" to denote a variable amino acid. The crystal structure of G6PD reveals an extensive network of electrostatic interactions and hydrogen bonding involving G6P, 3 water molecules, 3 lysines , 1 arginine , 2 histidines , 2 glutamic acids , and other polar amino acids. The proline at position 172

4070-470: The exterior of proteins, where it can interact with the aqueous environment. Lysine can also contribute to protein stability as its ε-amino group often participates in hydrogen bonding , salt bridges and covalent interactions to form a Schiff base . A second major role of lysine is in epigenetic regulation by means of histone modification . There are several types of covalent histone modifications, which commonly involve lysine residues found in

4144-436: The formation of the penultimate product, meso ‑diaminopimelate, which is subsequently enzymatically decarboxylated in an irreversible reaction catalysed by diaminopimelate decarboxylase (DAPDC) (E.C 4.1.1.20) to produce L -lysine. The DAP pathway is regulated at multiple levels, including upstream at the enzymes involved in aspartate processing as well as at the initial DHDPS catalysed condensation step. Lysine imparts

4218-495: The growth of AML cell lines. G6PD is hypomethylated at K403 in acute myeloid leukemia , SIRT2 activates G6PD to enhance NADPH production and promote leukemia cell proliferation. Pentose phosphate pathway The pentose phosphate pathway (also called the phosphogluconate pathway and the hexose monophosphate shunt or HMP shunt ) is a metabolic pathway parallel to glycolysis . It generates NADPH and pentoses (five- carbon sugars ) as well as ribose 5-phosphate ,

4292-574: The intentional dysregulation of the DAP pathway by means of introducing lysine feedback-insensitive orthologues of the DHDPS enzyme. These methods have met limited success likely due to the toxic side effects of increased free lysine and indirect effects on the TCA cycle. Plants accumulate lysine and other amino acids in the form of seed storage proteins , found within the seeds of the plant, and this represents

4366-407: The malarial parasite Plasmodium falciparum among individuals of Mediterranean and African descent. The basis for this resistance may be a weakening of the red cell membrane (the erythrocyte is the host cell for the parasite) such that it cannot sustain the parasitic life cycle long enough for productive growth. Lysine Lysine (symbol Lys or K ) is an α-amino acid that

4440-463: The most common of which is the saccharopine pathway . Lysine plays several roles in humans, most importantly proteinogenesis , but also in the crosslinking of collagen polypeptides, uptake of essential mineral nutrients, and in the production of carnitine , which is key in fatty acid metabolism . Lysine is also often involved in histone modifications , and thus, impacts the epigenome . The ε-amino group often participates in hydrogen bonding and as

4514-520: The other hand, it was shown that the presence of NADP at the structural site promotes the dimerization of dimers to form enzyme tetramers. It was also thought that the tetramer state was necessary for catalytic activity; however, this too was shown to be false. The NADP structural site is quite different from the NADP catalytic coenzyme binding site, and contains the nucleotide-binding fingerprint. The structural site bound to NADP possesses favorable interactions that keep it tightly bound. In particular, there

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4588-504: The pentose phosphate pathway, and the carbon skeletons of dietary carbohydrates may be converted into glycolytic/gluconeogenic intermediates. In mammals, the PPP occurs exclusively in the cytoplasm. In humans, it is found to be most active in the liver, mammary glands, and adrenal cortex. The PPP is one of the three main ways the body creates molecules with reducing power, accounting for approximately 60% of NADPH production in humans. One of

4662-416: The positioning of Arg487 relative to NADP, and thus disrupt binding. G6PD converts G6P into 6-phosphoglucono-δ-lactone and is the rate-limiting enzyme of the pentose phosphate pathway . Thus, regulation of G6PD has downstream consequences for the activity of the rest of the pentose phosphate pathway . Glucose-6-phosphate dehydrogenase is stimulated by its substrate G6P. The usual ratio of NADPH/NADP in

4736-590: The protruding tail of histones. Modifications often include the addition or removal of an acetyl (−CH 3 CO) forming acetyllysine or reverting to lysine, up to three methyl (−CH 3 ) , ubiquitin or a sumo protein group. The various modifications have downstream effects on gene regulation , in which genes can be activated or repressed. Lysine has also been implicated to play a key role in other biological processes including; structural proteins of connective tissues , calcium homeostasis , and fatty acid metabolism . Lysine has been shown to be involved in

4810-587: The reduction of glutathione. Hydrogen peroxide is also generated for phagocytes in a process often referred to as a respiratory burst . In this phase, two molecules of NADP are reduced to NADPH , utilizing the energy from the conversion of glucose-6-phosphate into ribulose 5-phosphate . The entire set of reactions can be summarized as follows: The overall reaction for this process is: Net reaction: 3 ribulose-5-phosphate → 1 ribose-5-phosphate + 2 xylulose-5-phosphate → 2 fructose-6-phosphate + glyceraldehyde-3-phosphate Glucose-6-phosphate dehydrogenase

4884-402: The structural site, thus affecting the long term stability of these enzymes in the body, ultimately resulting in G6PD deficiency. For example, two severe class I mutations, G488S and G488V, drastically increase the dissociation constant between NADP and the structural site by a factor of 7 to 13. With the proximity of residue 488 to Arg487, it is thought that a mutation at position 488 could affect

4958-422: The structurally simpler leucine, and M to methionine. Two pathways have been identified in nature for the synthesis of lysine. The diaminopimelate (DAP) pathway belongs to the aspartate derived biosynthetic family, which is also involved in the synthesis of threonine , methionine and isoleucine , whereas the α-aminoadipate (AAA) pathway is part of the glutamate biosynthetic family. The DAP pathway

5032-551: The structures of other mutants. For example, in German ancestry, where enzymopathy due to G6PD deficiency is rare, mutation sites on G6PD have been shown to lie near the NADP binding site, the G6P binding site, and near the interface between the two monomers. Thus, mutations in these critical areas are possible without completely disrupting the function of G6PD. In fact, it has been shown that most disease causing mutations of G6PD occur near

5106-412: The subsequent purification of lysine. Good sources of lysine are high-protein foods such as eggs, meat (specifically red meat, lamb, pork, and poultry), soy , beans and peas, cheese (particularly Parmesan), and certain fish (such as cod and sardines ). Lysine is the limiting amino acid (the essential amino acid found in the smallest quantity in the particular foodstuff) in most cereal grains , but

5180-585: The treatment for HSV outbreaks. In response to product claims that lysine could improve immune responses to HSV, a review by the European Food Safety Authority found no evidence of a cause–effect relationship. The same review, published in 2011, found no evidence to support claims that lysine could lower cholesterol, increase appetite, contribute to protein synthesis in any role other than as an ordinary nutrient, or increase calcium absorption or retention. Diseases related to lysine are

5254-427: The uses of NADPH in the cell is to prevent oxidative stress . It reduces glutathione via glutathione reductase , which converts reactive H 2 O 2 into H 2 O by glutathione peroxidase . If absent, the H 2 O 2 would be converted to hydroxyl free radicals by Fenton chemistry , which can attack the cell. Erythrocytes, for example, generate a large amount of NADPH through the pentose phosphate pathway to use in

5328-434: The α-carbon is in the S configuration. The human body cannot synthesize lysine. It is essential in humans and must therefore be obtained from the diet. In organisms that synthesise lysine, two main biosynthetic pathways exist, the diaminopimelate and α-aminoadipate pathways, which employ distinct enzymes and substrates and are found in diverse organisms. Lysine catabolism occurs through one of several pathways,

5402-453: Was first isolated by the German biological chemist Ferdinand Heinrich Edmund Drechsel in 1889 from hydrolysis of the protein casein , and thus named it Lysin, from Greek λύσις (lysis)  'loosening'. In 1902, the German chemists Emil Fischer and Fritz Weigert determined lysine's chemical structure by synthesizing it. The one-letter symbol K was assigned to lysine for being alphabetically nearest, with L being assigned to

5476-451: Was proposed that an auxotrophic strain of Escherichia coli ( X 1776) could be used for all genetic modification practices, as the strain is unable to survive without the supplementation of DAP, and thus, cannot live outside of a laboratory environment. Lysine has also been proposed to be involved in calcium intestinal absorption and renal retention, and thus, may play a role in calcium homeostasis . Finally, lysine has been shown to be

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