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22.3: Molecules Derived from Amino Acids

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    15180
  • Following from:Lieu, E.L., Nguyen, T., Rhyne, S. et al. Amino acids in cancer. Exp Mol Med 52, 15–30 (2020).

     

    Amino acids provide both carbon and nitrogen for nucleic acid synthesis (Fig. 2c). Purine biosynthesis requires formate, bicarbonate, and three amino acids: aspartate, glycine, and glutamine. While glutamine and aspartate act as the nitrogen source for both nucleobases (N1 from aspartate and N3 and N9 from glutamine) and the amino group of purines (glutamine for adenine and aspartate for guanine), glycine can contribute to purine biosynthesis in two ways: by direct incorporation into the purine backbone (C4, C5, and N7) or by producing one-carbon units for biochemical reactions involved in purine biosynthesis (C2 and C8) (Fig. 2c)5. The critical carrier of one-carbon units in the latter process is 5,10-meTHF. 5,10-meTHF is further converted to formate (10-formyl THF), contributing C2 and C8 carbons to the nucleobase4,7,61. Pyrimidine biosynthesis is simpler than that of purine. In contrast to purines that are synthesized as ribonucleotides rather than as nucleobases, pyrimidines are synthesized first as nucleobases and then conjugated to phosphoribosyl pyrophosphate (PRPP) to yield the corresponding ribonucleotide. The pyrimidine ring is derived from glutamine, aspartate, and bicarbonate. For pyrimidine synthesis, aspartate acts as both carbon and nitrogen donors (N1, C4, C5, and C6), whereas glutamine contributes to N3 of the nucleobase and amino group of cytosine (Fig. 2c)4. The one-carbon unit derived from serine to glycine conversion is required for thymidylate synthesis. 5,10-meTHF serves as a one-carbon donor to transfer a methyl group to deoxyuridine monophosphate (dUMP) and produce deoxythymidine monophosphate (dTMP), a reaction catalyzed by thymidylate synthase (TS)7,8.

    In addition to their primary role in the biosynthesis of nitrogenous metabolites, amino acids can supply carbon atoms for lipid biosynthesis. Under hypoxia, glutamine contributes to the acetyl-CoA pools needed for lipogenesis by being converted into pyruvate that reenters the TCA cycle46,62. BCAAs can also contribute to lipogenesis. In differentiated adipocytes, BCAA catabolic flux increases, and BCAA-derived acetyl-CoA accounts for approximately 30% of the lipogenic acetyl-CoA pools3,63. Essential amino acids (EAAs) act not only as carbon donors, but their ratio can also regulate lipogenesis by impacting lipogenic gene expression64. In bovine mammary epithelial cells, the “optimal” amino acid (AA) ratio (OPAA = Lys:Met 2.9:1; Thr:Phe 1.05:1; Lys:Thr 1.8:1; Lys:His 2.38:1; Lys:Val 1.23:1) upregulates lipogenic gene expression and alters the expression of key miRNAs involved in the control of lipogenic balance, implying a potentially important role of EAA ratios in lipid synthesis64. It would be interesting to see if this is conserved in other species as well as in cancer.

    a Reverse-transsulfuration pathway: Cysteine can be produced from methionine through the reverse-transsulfuration pathway. This pathway is a combination of the methionine cycle and transsulfuration pathway. Homocysteine, the intermediate of the first step in the transsulfuration pathway, is generated from the methionine cycle. Serine condenses with homocysteine, producing cystathionine. Cystathionine is then converted to cysteine and alpha-ketobutyrate by CGL. Key enzymes are in red circle. THF tetrahydrofolate, CBS cystathionine β-synthase, SAM S-adenosylmethionine, CGL cystathionine γ-lyase. b Polyamine synthesis: Polyamines (putrescine, spermine, and spermidine) are synthesized from the amino acid arginine, and are converted from one to another (in the order of putrescine to spermidine to spermine). SAM, as the precursor of dcSAM, is the major donor for constructing polyamine structures. Key enzymes are in red circle. ODC ornithine decarboxylase, AMD S-adenosylmethionine decarboxylase, SAM S-adenosylmethionine, dcSAM decarboxylated S-adenosylmethionine. c Nitrogen and carbon source for nucleic acids: Aspartate, glycine, and glutamine provide nitrogen, and glycine and one-carbon units from the folate cycle (as a form of formate) provide carbon for purines. Glycine is formate’s indirect precursor through one-carbon metabolism, providing formate for biochemical reactions in purine biosynthesis. Aspartate and glutamine are the main amino acids involved in pyrimidine synthesis. Carbon (C) is in yellow, and nitrogen (N) is in green. d GSH and NADPH as antioxidants: Reactive oxygen species (ROS) bind and damage cellular macromolecules. The oxidation of NADPH and GSH allows ROS to be reduced to an inactive state. GSH reduces hydrogen peroxide to water and becomes oxidized to GSSG by GPX. Oxidized glutathione (GSSG) is then reduced back to GSH by GR in the presence of NADPH. Enzymes are shown in red circles. GPX glutathione peroxidase, GR glutathione reductase, GSH reduced glutathione, GSSG oxidized glutathione, NADPH reduced nicotinamide adenine dinucleotide phosphate, NADP+ oxidized nicotinamide adenine dinucleotide phosphate. e Amidation reaction for asparagine synthesis: Asparagine is synthesized by an amidotransferase reaction, catalyzed by asparagine synthetase (ASNS). The conserved amide group nitrogen is in a red box, while the enzyme is in a red circle.

    Fig. 2

     

    This figure has been adapted from Lieu, E.L., Nguyen, T., Rhyne, S. et al. Amino acids in cancer. Exp Mol Med 52, 15–30 (2020). https://doi.org/10.1038/s12276-020-0375-3,  This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.  To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

     

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    Amino acid catabolism produces metabolic intermediates affecting tumor cell growth and survival. Polyamines (putrescine, spermine, and spermidine) might be the best-known metabolites to promote tumor proliferation and aggressiveness65. Polyamine synthesis starts from arginine conversion to ornithine through the action of arginase, which is then decarboxylated by the rate-limiting step enzyme, ornithine decarboxylase (ODC), to produce putrescine (Fig. 2b). Decarboxylated S-adenosylmethionine, catalyzed by S-adenosylmethionine decarboxylase (AMD)66, then donates its propyl amine moiety to putrescine and spermidine for the formation of spermidine and spermine, respectively (Fig. 2b)67. Elevated polyamine levels have been observed in patients with cancer. Polyamines and their metabolites in urine and plasma can be useful in both cancer diagnosis and as markers of tumor progression in lung and liver cancers68,69. Polyamines affect numerous processes in tumorigenesis, in part by regulating specific gene expression transcriptionally. As charged cations at physiological pH, polyamines can associate with nucleic acids70, which in turn can affect global chromatin structure71 as well as specific DNA–protein interactions72, leading to impacts on gene transcription. Posttranscriptional aspects of polyamine-mediated gene regulation are associated with the eukaryotic translation initiation factor 5A (eIF5A), whose expression/function is strongly correlated with unfavorable prognostic implications for several cancers73,74,75. The spermidine-derived amino acid hypusine, a unique eIF5A posttranslational modification of lysine residue 50, is essential for eIF5A functions76. Polyamines also exist as a polyamine-RNA complex77. Polyamine binding to RNA leads to structural changes, which stimulate and increase the efficiency of protein synthesis.

    Nitric oxide (NO) is another metabolic consequence of arginine catabolism. Depending on its timing, location, and concentration, it has both tumor-suppressive and tumor-promoting effects78. It promotes tumor growth through multiple mechanisms, including increasing angiogenesis and limiting the host immune response against tumors. It can, however, also act as a tumor-suppressive molecule by activating caspases and upregulating tumor suppressor p5378. Thus, a better understanding of NO biology and further validation with molecular and clinical studies are necessary to develop NO-based strategies for cancer prevention and treatment.

    Kynurenine is a tumor-associated metabolite that is catabolized from tryptophan by tryptophan 2,3-dioxygenase (TDO) and indoleamine 2,3-dioxygenase (IDO)79. An increased kynurenine to tryptophan ratio has been observed in various tumors, including Hodgkin lymphoma, lung cancer, and ovarian cancer80,81,82. The important role of kynurenine is linked to its ability to suppress antitumor immune responses. Kynurenine secreted from tumors induces cytotoxic CD8 T-cell death, enhancing immune evasion during metastasis10. Importantly, kynurenine-mediated immunosuppression is not limited to cross talk between cancer cells and immune cells (Fig. 3c). Communication within the different immune cells also regulates their kynurenine synthesis11,15. Regulatory T (TR) cells activate IDO in DCs, priming DCs for tolerance induction through CTLA-4 (resting TR cells) or IFN-γ (CD3-activated TR cells) (Fig. 3c)11,15. As immunometabolic adjuvants to widen therapeutic windows, IDO inhibitors may leverage not only immuno-oncology modalities but also conventional chemotherapy and/or radiotherapy.

     

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    Amino acids for redox balance

    Cancer cells inevitably produce high levels of reactive oxygen species (ROS) due to their highly proliferative nature. ROS are intracellular chemical species containing oxygen and include the superoxide anion (O2), hydrogen peroxide (H2O2), and the hydroxyl radical (OH·). Oxygen radicals produced from ROS can covalently bind to and oxidize macromolecules (lipids, proteins, and DNA), leading to cellular damage (Fig. 2d). Consequently, increased ROS production requires coupling with increased antioxidant defense production to protect cancer cells from ROS-mediated demise; thus, cancer cells allocate significant energy to maintain their intracellular redox balance. Key metabolic players that control the redox state are reduced nicotinamide adenine dinucleotide phosphate (NADPH) and reduced glutathione (GSH) (Fig. 2d). NADPH is a cofactor that not only provides reducing power for macromolecule biosynthesis, but also functions as an antioxidant by acting as a hydride (hydrogen anion) donor in various enzymatic processes, including reduction of glutathione disulfide (GSSG) back to GSH (Fig. 2d). GSH is an essential thiol antioxidant and plays a key role in controlling the redox state of all subcellular compartments85. GSH reduces hydrogen peroxide to water and becomes oxidized to GSSG in the presence of GSH peroxidase (GPX) (Fig. 2d). Oxidized glutathione (GSSG) is then reduced back to GSH by glutathione reductase (GR) and NADPH. Amino acids are the main elements for GSH synthesis and NADPH generation. Glutathione synthesis requires three amino acids: glutamate, glycine, and cysteine. Among them, cysteine is the key element because of its thiol group (R-SH), which has redox properties. Inhibiting cysteine uptake reduces viability due to cell death caused by uncontrolled oxidative stresses17,18,86. Cysteine can be imported into cells either directly or in its oxidized form, cystine, through the cystine/glutamate antiporter system xc (xCT). Once in the cell, cystine is immediately reduced to cysteine either by intracellular GSH via the formation of a mixed disulfide intermediate or by thioredoxin reductase 1 (TRR1)87. The rate-limiting step of glutathione synthesis is the ATP-dependent condensation of cysteine and glutamate to form the dipeptide γ-glutamylcysteine by glutamate cysteine ligase (GCL)88. Glycine is then added to the C-terminal of γ-glutamylcysteine to produce glutathione.

     

    HVJ added: Glutathione Synthesis

    Glutathione_Synthesis.png

     

    The reducing equivalent NADPH is required to maintain multiple antioxidant defense systems. It has been generally accepted that the main route to produce cellular NADPH is glucose via the pentose phosphate pathway (PPP). However, a growing body of research has uncovered that serine-driven one-carbon metabolism via the folate cycle contributes nearly as much to NADPH production as the PPP and malic enzymes in proliferating cells19. In the folate cycle, serine to glycine conversion produces 5,10-meTHF, which is oxidized to 10-formyl-tetrahydrofolate (formate/10-formyl THF)6. The latter reaction is coupled to the reduction of NADP+ to NADPH. SHMT-mediated serine catabolism, especially mitochondrial SHMT2 reaction, is critical for redox regulation under hypoxia89. SHMT2 is induced by hypoxic stress through HIF1α and is involved in maintaining the cellular NADPH/NADP+ ratio89. Serine is also involved in GSH synthesis via the folate cycle90. In addition to NADPH production, the folate cycle contributes to the production of GSH by intersecting with the methionine cycle6. Thus, it is not surprising that serine depletion results in glutathione reduction91. Indeed, activation of serine synthesis is now well identified as a bypass of glycolytic flux contributing to GSH synthesis92,93. Considering the importance of amino acids in redox homeostasis, the transport and internal synthesis pathways for cysteine, serine, glutamine, and to some extent glycine would be legitimate targets for the development of novel redox-based therapeutics.

     

    Heme Biosynthesis

    Following from:

    Biochemistry, Heme Synthesis,  Aminat S. Ogun; Neena V. Joy; Menogh Valentine.  https://www.ncbi.nlm.nih.gov/books/NBK537329/  

    Introduction

    Heme is a porphyrin ring complexed with ferrous iron and protoporphyrin IX. Heme is an essential prosthetic group in proteins that is necessary as a subcellular compartment to perform diverse biological functions like hemoglobin and myoglobin. Other enzymes which use heme as a prosthetic group includes cytochromes of the electron transport chain, catalase, and nitric oxide synthase. The major tissues for heme synthesis are bone marrow by erythrocytes and the liver by hepatocytes.

    Fundamentals

    Heme synthesis occurs in the cytosol and mitochondria; heme acquisition also occurs through intestinal absorption and intercellular transport. Heme is a component of different biological structures mainly, hemoglobin, others include myoglobin, cytochromes, catalases, heme peroxidase, and endothelial nitric oxide synthase. There are different forms of biological heme. The most common type is heme b, found in hemoglobin leads to a derivative of other heme groups. Heme a exists in cytochrome a and heme c in cytochrome c; they are both involved in the process of oxidative phosphorylation.

    5'-Aminolevulinic acid synthase (ALA-S) is the regulated enzyme for heme synthesis in the liver and erythroid cells. There are two forms of ALA Synthase, ALAS1, and ALAS2. All cells express ALAS1 while only the liver and bone marrow expresses ALAS2. The gene for ALAS2 is on the X-chromosome.

    Cellular

    Porphyrin synthesis is the process that produces heme. Heme synthesis occurs partly in the mitochondria and partly in the cytosol. The biosynthesis involves an eight-step enzymatic pathway. Heme biosynthesis starts in mitochondria with the condensation of succinyl Co-A from the citric acid cycle and an amino acid glycine. They combine to produce a key heme intermediate, 5'-aminolevulinic acid (ALA) in mitochondria catalyzed by the pyridoxal phosphate-requiring (vitamin B6) enzyme, aminolevulinic acid synthase (ALAS). This reaction is the rate-limiting step in the pathway.

    The ALA molecule formed exit the mitochondria into the cytosol where two molecules of ALA condense to produce the pyrrole ring compound porphobilinogen (PBG) catalyzed by a zinc-requiring enzyme, ALA dehydratase enzyme (also called porphobilinogen synthase). The next step of the pathway involves condensation of four molecules of porphobilinogen, aligned to form the linear hydroxymethylbilane (HMB), catalyzed by porphobilinogen deaminase (PBG deaminase) also known as hydroxymethylbilane synthase. 

    Closure of the linear HMB forms an asymmetric pyrrole ring D called uroporphyrinogen III, catalyzed by uroporphyrinogen-III synthase. This step is vital as an incorrect porphyrin ring formation leads to protoporphyria. The correct porphyrin ring III forms, and then the side chains of uroporphyrinogen III are modified, catalyzed by uroporphyrinogen decarboxylase to produce coproporphyrinogen III.

    Following its synthesis, coproporphyrinogen III gets transported into mitochondria. The coproporphyrinogen III then gets decarboxylated by coproporphyrinogen oxidase enzyme to form the colorless product protoporphyrinogen IX. 

    Finally, protoporphyrinogen IX is converted to protoporphyrin IX using protoporphyrinogen oxidase.  The final reaction involves the insertion of ferrous iron into protoporphyrin IX catalyzed by the enzyme ferrochelatase leading to the formation of heme.

    Image below from: Wikimedia Commonsile:Heme-Synthesis-Chemical-Details-Mirror.svg

    Heme-Synthesis-Chemical-Details-Mirror (2)_pdftoPhotoshop.png

    HVJ

    Here is a likely mechanism for the 1st committed step - the productin of ALA.  This is used in the sythesis of all tetrapyrols, include heme, chlorophyll and cobalamins.

     

    ALASynthase_Reaction_Mechanism_Image.jpgabove image from  Aminolevulinic acid synthase, Wikipedia.  https://en.wikipedia.org/wiki/Aminol..._acid_synthase

    next pargraph from:

    In nature, there exist two known alternate routes by which this committed intermediate is generated2,3. One route is the C4 pathway (Shemin pathway), which involves the condensation of succinyl-CoA and glycine to ALA by ALA synthase (ALAS). The C4 pathway is restricted to mammals, fungi and purple nonsulfur bacteria4. The second route is the C5 pathway5, which involves three enzymatic reactions resulting in the biosynthesis of ALA from glutamate. The C5 pathway is active in most bacteria, all archaea and plants  .  

    Scientific Reports volume 5, Article number: 8584 (2015)

    Then continue with cited text:

     

    Heme synthesis in erythroid cells: heme is synthesized for incorporation into hemoglobin. In immature erythrocytes (reticulocytes), heme stimulates protein synthesis of the globin chains and erythropoietin stimulates heme. The kidney releases erythropoietin hormone at low oxygen levels in tissues and stimulates RBC and hemoglobin synthesis. Accumulation of heme in erythroid cells is desired as it leads to more globin chain synthesis and required in erythroblast maturation. When red cells mature both heme and hemoglobin synthesis ceases.  Additionally, control of heme biosynthesis in erythrocytes is controlled by the availability of intracellular iron.

    Heme synthesis in the liver is highly variable and tightly regulated as heme outside proteins causes damage to hepatocytes at high concentration. In the liver, cytochrome P450 (CYP 450) requires heme. Liver contains the isoform ALAS1 which is expressed in most cells. Drugs increase ALAS1 activity as they lead to CYP 450 synthesis which needs heme. Low intracellular heme concentration stimulates synthesis of ALAS1. Heme synthesis stops when heme is not incorporated into proteins and when heme and hemin accumulate.

    Hemin decreases the synthesis of ALA synthase 1 in three ways: Hemin reduces the synthesis of ALAS1 mRNA, destabilizes ALAS1 mRNA, and inhibits import of the enzyme ALAS1 from the cytosol into mitochondria.

    Pathophysiology

    A defect or mutation in 5’- aminolevulinic acid synthase 2 (ALAS2) leads to a disorder called X-linked sideroblastic anemia. It reduces protoporphyrin production and decreases heme. However, Iron continues to enter the erythroblast leading to an accumulation in the mitochondria and therefore a manifestation of the disease.

    During the biosynthetic pathway, the linear hydroxymethylbilane can spontaneously form a “faulty” porphyrin ring when not immediately used as a substrate for uroporphyrinogen synthesis. If uroporphyrinogen III synthase is deficient, then hydroxymethylbilane spontaneously closes and forms a different molecule called uroporphyrinogen I. Uroporphyrinogen leads to the formation of coproporphyrinogen I. This molecule does not result in the formation of heme. 

     

    Above:  distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits use, duplication, adaptation, distribution, and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, a link is provided to the Creative Commons license, and any changes made are indicated.

     

    1920px-Heme_synthesis.svg.png

    Figure above from Heme synthesis.png, https://commons.wikimedia.org/wiki/F..._synthesis.png

     

    More detail figure:  sythesis of Hb

     

    Neurotransmitters

    Section below modified from https://www.intechopen.com/books/neu...rotransmitters .  in Synaptic Transmission and Amino Acid Neurotransmitters.  This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License,

    By Manorama Patri

    The three major categories of amino acids and their derivatives act as neurotransmitters are:

    1. Amino acids: The neurotransmitters of this group are involved in fast synaptic transmission and are inhibitory and excitatory in action (primarily glutamic acid, GABA, aspartic acid, and glycine).

    2. Amines: Amines are the modified amino acids such as biogenic amines, e.g., catecholamines. The neurotransmitters of this group involve in slow synaptic transmission and are inhibitory and excitatory in action (noradrenaline, adrenaline, dopamine, serotonin, and histamine).

    3. Others: The one which do not fit in any of these categories (acetyl choline and nitric oxide). Amino acids are among the most abundant of all neurotransmitters present within the central nervous system (CNS).

    Amino acid transmitters provide the majority of excitatory and inhibitory neurotransmission in the nervous system. Amino acids used for synaptic transmission are compartmentalized (e.g., glutamate, compartmentalized from metabolic glutamate used for protein synthesis by packaging the transmitter into synaptic vesicles for subsequent Ca2+-dependent release). Amino acid neurotransmitters are all products of intermediary metabolism with the exception of GABA. Unlike all the other amino acid neurotransmitters, GABA is not used in protein synthesis and is produced by an enzyme (glutamic acid decarboxylase; GAD) uniquely located in neurons.

     

    Here is some more specific information:

    • Glutamate:  Glutamate is used at the great majority of fast excitatory synapses in the brain and spinal cord.  Glutamates binds to glutamate receptors of which there are many subtypes based on other molecules (some amino acid derivatives) that can bind to them. These other molecules include N-methyl-D-aspartate (NMDA), α-amino-3-hydroxy-5-methyl-4-isoxazolepropionate (AMPA) kainate and quisqualate.  
    • Asparatate: Aspartate is the most abundant excitatory neurotransmitter in the CNS. Like glycine, aspartate is primarily localized to the ventral spinal cord.  Note that the two major excitatory neurotransmitters both have carboxyllc acid side chains.
    • Gamma aminobutyric acid (GABA):  GABA, which is not one of the canconical amino acids used in protein biosynthesis, is the most ubiquitous inhibitory neurotransmitter in the brain.  
    • Glycine:  lycine receptors are ligand-gated ion channels that increase Cl influx and hence are generally inhibitory. Hydroxymethyl transferase converts the amino acid serine to glycine. Glycine has been found to play a role in the functional modulation of NMDA receptors

     

    Neurotransmitters:  Bioactive amines;

    my figure

    MonomamineStructures.png

     

    Below not Creative Commons:

    he Biogenic Amines

    There are five established biogenic amine neurotransmitters: the three catecholamines—, norepinephrine (noradrenaline), and —and  and  (see Figure 6.3). In terms of synthesis, packaging, release, and degradation, the amine neurotransmitters fall somewhere between the properties of the other small-molecule neurotransmitters and those of the .

    All the catecholamines (so named because they share the catechol moiety) are derived from a common precursor, the amino acid tyrosine (Figure 6.11). The first step in  synthesis is catalyzed by tyrosine hydroxylase in a reaction requiring oxygen as a co-substrate and tetrahydrobiopterin as a cofactor to synthesize dihydroxyphenylalanine (DOPA). Because tyrosine hydroxylase is rate-limiting for the synthesis of all three transmitters, its presence is a valuable criterion for identifying catecholaminergic neurons.

    Figure 6.11. The biosynthetic pathway for the catecholamine neurotransmitters.

    Figure 6.11

    The biosynthetic pathway for the catecholamine neurotransmitters. The amino acid tyrosine is the precursor for all three catecholamines. The first step in this reaction pathway, catalyzed by tyrosine hydroxylase, is rate-limiting.

    • Dopamine is produced by the action of DOPA decarboxylase on DOPA (see Figure 6.11). Although present in several brain regions (Figure 6.12A), the major -containing area of the brain is the , which receives major  from the  and plays an essential role in the coordination of body movements. In Parkinson's disease, for instance, the dopaminergic neurons of the substantia nigra degenerate, leading to a characteristic  dysfunction (see Box B in Chapter 18). Although dopamine does not readily cross the , its precursor, levodopa, does. Levodopa is absorbed in the small bowel but is rapidly catabolized in the GI tract and in peripheral tissues. Hence, the disease can be treated by administering levodopa together with carbidopa, a dopamine decarboxylase inhibitor, and selegiline, a monoamine oxidase inhibitor. Dopamine is also believed to be involved in motivation, reward, and reinforcement. For example, cocaine and other addictive drugs act by stimulating the release of dopamine from specific brain areas (see Box D). Once released, dopamine binds to specific dopamine receptors, as well as to some β- receptors. It not only acts as a  in the  but also plays a poorly understood role in some sympathetic ganglia. Dopamine is also used clinically to treat shock because it dilates renal arteries by activating dopamine receptors and increases cardiac output by activating β-adrenergic receptors in the heart.

    • Norepinephrine (also called noradrenaline) synthesis requires  β-hydroxylase, which catalyzes the production of norepinephrine from dopamine (see Figure 6.11). Dopamine is transported by vesicles into  terminals, where it is converted to norepinephrine. The most prominent  of neurons that synthesize norepinephrine is sympathetic ganglion cells, since norepinephrine is the major peripheral  in this division of the  (see Chapter 21). Norepinephrine is also the transmitter used by the , a  nucleus that projects diffusely to a variety of  targets (Figure 6.12B), where it influences sleep and wakefulness, , and feeding behavior.

    • Epinephrine (also called ) is present in the brain at lower levels than the other catecholamines. The enzyme that synthesizes epinephrine, phenylethanolamine-N-methyltransferase (see Figure 6.11), is present only in epinephrine-secreting neurons. Epinephrine-containing neurons in the  are found in two groups in the  , the function of which is not known.

      All three catecholamines are removed by reuptake into  terminals or surrounding glial cells by a Na+-dependent transporter. The two major enzymes involved in the catabolism of catecholamines are monoamine oxidase (MAO) and catechol O-methyltransferase (COMT). Both neurons and glia contain mitochondrial MAO and cytoplasmic COMT. Inhibitors of these enzymes, such as phenelzine and tranylcypromine, are used clinically as antidepressants (see Box C).

    • Histamine is produced from the amino acid histidine by a histidine decarboxylase and is metabolized by the combined actions of  methyltransferase and MAO. (Figure 6.13A). High concentrations of histamine and histamine decarboxylase are found in neurons in the  that send sparse but widespread projections to almost all regions of the brain and  (see Figure 6.12C). The central histamine projections mediate arousal and , similar to central ACh and norepinephrine projections. This partly explains why antihistamines that cross the , such as diphenhydramine (Benadryl®), act as sedatives. Histamine also is released from mast cells in response to allergic reactions or tissue damage. The close proximity of mast cells to blood vessels, together with the potent actions of histamine on blood vessels, raises the possibility that histamine may influence brain blood flow.

    • Serotonin, or 5-hydroxytryptamine (5-HT), was initially thought to increase vascular tone by virtue of its presence in serum (hence the name ). 5-HT is synthesized from the amino acid tryptophan, which is an essential dietary requirement. Tryptophan is taken up into neurons by a plasma membrane transporter and hydroxylated in a reaction catalyzed by the enzyme tryptophan-5-hydroxylase (Figure 6.13B), the rate-limiting step for 5-HT synthesis. As in the case of other , the synaptic effects of serotonin are terminated by transport back into serotonergic  terminals. The primary catabolic pathway is mediated by MAO. Serotonin is located in groups of neurons in the raphe region of the  and upper , which have widespread projections to the  (see Figure 6.12D) and have been implicated in the regulation of sleep and wakefulness (see Chapter 28). A number of antipsychotic drugs used in the treatment of depression and anxiety are thought to act specifically on serotonergic neurons.

      Because  are implicated in such a wide range of behaviors (ranging from central homeostatic functions to cognitive phenomena such as ), it is not surprising that drugs affecting the synthesis,  binding, or catabolism of these neurotransmitters are among the most important in the armamentarium of modern pharmacology (Box C).

    make this image: https://www.researchgate.net/publica...s/figures?lo=1

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