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Outside the brain, the major site of norepinephrine and epinephrine synthesis is in adrenal medullary chromaffin cells. Neuronal NOS (nNOS) is constitutively expressed in specific neurons within the brain and spinal cord.
GSH is synthesized in the cytosol of all mammalian cells via the two-step reaction shown in the Figure. The polyamines are highly cationic molecules that tend to bind nucleic acids with high affinity. An important intermediate required for the synthesis of spermidine and spermine from putrescine is derived from S-adenosylmethionine (SAM). The AMD1 gene is located on chromosome 6p21 and is composed of 10 exons that generate four alternatively spliced mRNAs that encode four distinct isoforms of the enzyme. The stability of the ODC1 protein also contributes to the level of enzyme activity in cells.
Antizyme 2 is encoded by the OAZ2 gene which is located on chromosome 15q22.31 and is composed of 5 exons that generate two alternatively spliced mRNAs that encode two distinct protein isoforms.
As discussed, the synthesis of the polyamines is regulated by several independent mechanisms. Anyone can submit a comment any time after publication, but only those submitted within 4 weeks of an article’s publication will be considered for print publication.
The inorganic anion nitrite (NO2-) can be metabolized in blood and tissues to form nitric oxide (NO), a pluripotent biological messenger. Within the locus coeruleus region of the brain the end product of the pathway is norepinephrine. Segawa syndrome is an autosomal recessive disorder that manifests in early infancy as a DOPA-responsive dystonia. DOPA decarboxylase (also known as aromatic L-amino acid decarboxylase) is encoded by the DDC gene.
The major location, within the brain, for norepinephrine synthesis is the locus coeruleus of the brainstem. Outside the brain, dopamine is synthesized in several tissues including the gastrointestinal system where its actions reduce gastrointestinal motility, the pancreas where its actions inhibit insulin synthesis, and in the kidneys where its actions increase sodium excretion and urinary output. Tryptophan hydroxylase represents the rate-limiting step in serotonin and melatonin synthesis.
Histamine is synthesized by the enzymatic decarboxylation of the amino acid histidine by the enzyme L-histidine decarboxylase (HDC).
The isoform 1 protein is composed of 662 amino acids and the isoform 2 protein is composed of 629 amino acids. The NOS1 gene is located on chromosome 12q24.22 and is composed of 35 exons the generate multiple alternatively spliced mRNAs that encode three characterized isoforms. The NOS2 gene is located on chromosome 17q11.2 and is composed of 29 exons that encode a protein of 1153 amino acids.
The NOS3 gene is located on chromosome 7q36 and is composed of 29 exons that generate multiple alternatively spliced mRNAs that encode four characterized isoforms.
When intracellular Ca2+ levels rise the calmodulin subunits have an increased affinity for eNOS and nNOS. However, expression of eNOS is also detected in platelets, cardiac myocytes, specific renal tubular epithelial cells, certain neurons within the brain, and in placental syncytio-trophoblast cells. The cGMP, in turn, activates PKGI isoforms resulting in the phosphorylation of smooth muscle proteins that lead to relaxation. Although predominately induced in macrophages, under appropriate stimulation conditions many other cell types will express the iNOS gene. The formation of guanidinoacetate from these two amino acids is catalyzed by the enzyme glycine amidinotransferase, also called L-arginine:glycine amidinotransferase. These compounds form conjugates with GSH either spontaneously or enzymatically in reactions catalyzed by members of the glutathione S-transferase (GST) family. Because of this interaction activity, it is believed that the polyamines are important participants in DNA synthesis, or in the regulation of that process. The SMS gene is located on the X chromosome (Xp22.1) and is composed of 13 exons that generate two alternatively spliced mRNAs encoding SMS isoform 1 (366 amino acids) and SMS isoform 2 (313 amino acids).
The promoter of the ODC1 gene contains elements that are regulated by growth factors, hormones, and tumor promoters.
The half-life of ODC protein is short (< 1hr) and this half-life is controlled by proteosomal degradation.
In addition to the two different isoforms, the antizyme 1 mRNA contains two in-frame AUG codons that have been shown, in rodents, to be alternatively utilized resulting in differentially localized antizyme 1 isoforms.
In addition to these mechanism of control, intracellular polyamine levels are also regulated via their catabolism. Snyder, MD, Departments of Neuroscience, Pharmacology, and Molecular Sciences, The Johns Hopkins University School of Medicine, 725 North Wolfe Street, Baltimore, Maryland 21205. Calcium binds to calmodulin and activates endothelial cell nitric oxide synthase, which converts arginine plus oxygen into citrulline and nitric oxide.
Tumor necrosis factor-? binds to macrophages and activates intracellular proteins such as nuclear factor-? B (NF- ? B), which induce the transcription of nitric oxide synthase.
One month after publication, editors review all posted comments and select some for publication in the Letters section of the print version of Annals.
Nitrite reduction to NO is catalysed by various enzymatic and non-enzymatic pathways and is greatly enhanced during hypoxia and ischaemic stress, which may be of therapeutic value. Within adrenal medulla chromaffin cells, tyrosine is converted to norepinephrine and epinephrine.


Two distinct phenotypes are associated with Segawa syndrome, one that manifests very early and presents with symptoms of greater severity, and a later onset less severe type that responds better to L-DOPA therapy. Dopamine β-hydroxylase is a critical vitamin C (ascorbate) and copper (Cu2+)-dependent enzyme. The major brain region for the synthesis of dopamine is the substantia nigra which is located below the posterior hypothalamus and next to the ventral tegmetal area.
Within the gastrointestinal tract bacteria also produce histamine via a similar decarboxylation reaction.
The HRH1 gene is located on chromosome 3p25 and is composed of 8 exons that generate four alternatively spliced mRNAs all of which encode the same 487 amino acid protein.
The heme moiety of one monomer is indeed essential for the process of interdomain electron transfer between NADPH and the flavins (FAD and FMN) to the heme of the opposite monomer.
The calmodulin subunits facilitate the flow of electrons from NADPH to the heme moiety in the oxygenase domain of the enzyme.
The ability of eNOS produced NO to prevent platelet adhesion and aggregation reduces the propensity for the development of abnormal fibrin clots (thrombi) and, therefore, will contribute to a reduced potential for the development of atherosclerosis. Neuronal NOS is also constitutively expressed within the adrenal glands, pancreatic islet cells, epithelial cells of numerous tissues, vascular smooth muscle, skeletal muscle, and renal macula densa cells. Glycine amidinotransfersae is encoded by the GATM gene located on chromosome 15q21.1 and is composed of 12 exons that encode a 423 amino acid protein that localizes to the mitochondria.
The conjugates formed are usually excreted from the cell and, in the case of the liver they are excreted in the bile.
In addition to their function in DNA replication, polyamines and polyamine derivatives are involved in the processes of protein synthesis, ion channel function, regulation of gene expression, cell proliferation, and apoptosis (programmed cell death). Production of ODC protein is also regulated at the level of translation by the product of the reaction, putrescine. However, entry into the proteosome, in the case of ODC, does not require prior ubiquitination. Antizyme 3 is encoded by the OAZ3 gene which is located on chromosome 1q21.3 and is composed of 7 exons that generate three alternatively spliced mRNAs encoding three distinct protein isoforms. The constitutive isoforms found in endothelial cells and neurons release small amounts of nitric oxide for brief periods to signal adjacent cells, whereas the inducible isoform found in macrophages releases large amounts of nitric oxide continuously to eliminate bacteria and parasites. Nitric oxide diffuses out of the endothelial cell into an adjacent smooth muscle cell and activates guanylate cyclase by binding to the iron in its heme group. Once synthesized, macrophage nitric oxide synthase continuously makes nitric oxide, which can kill bacteria. In animal models, nitrite is strongly cytoprotective and protects against ischaemia–reperfusion injury. DOPA decarboxylase (also known as aromatic L-amino acid decarboxylase) is encoded by the DDC gene which is located on chromosome7p12.2 and is composed of 18 exons that generate multiple alternatively spliced mRNAs.
The presence of high concentrations of tyrosine in the locus coeruleus and the substantia nigra leads to increased melanin synthesis which confers on these brain regions a dark bluish coloration observable in brain sections. The principal cells that synthesize and release histamine are mast cells and basophils of the immune system, enterochromaffin-like cells of the gastrointestinal system, and neurons. The HRH2 gene is located on chromosome 5q35.2 and is composed of 8 exons that generate two alternatively spliced mRNAs. All three NOS enzymes function as homodimers and the interactions of the subunits is required for the process of electron flow from NADPH (bound in the reductase domain of the enzyme), through the various co-factors to the heme moiety which is bound to the N-terminal oxygenase domain of the enzyme. When intracellular Ca2+ rises it facilitates the binding of the calmodulin subunits to eNOS and nNOS. However, other factors regulate the activity of eNOS that are not related to changes in calcium concentrations. Endothelial cell produced NO can also interfere with leukocyte adhesion to the endothelium thus, further contributing to a reduction in the potential for atherosclerosis. Within the brain the principal functions of nNOS produced NO are in the mediation of long-term synaptic transmission. The production of large amounts of NO by activation of iNOS expression in macrophages represents the major cytotoxic activity of these cells.
Guanidinoacetate it transported to the blood and picked up by heptocytes where it is methylated forming creatine.
There are several GST enzymes that are divided into three major families that comprise cytsolic, mitochondrial, and microsomal family members.
The ODC1 mRNA contains a long 5'-untranslated region (5'-UTR) that folds into a complex secondary structure. The ability of the proteosome to recognize, and degrade, non-ubiquitinated ODC involves a family of proteins called antizymes. Antizyme 3 isoform 1 is the longest protein encoded by the OAZ3 gene and the translation of this form of the enzyme begins from a CUG codon and not an AUG codon. The SAT1 gene is located on the X chromosome (Xp22.1) and is composed of 7 exons that generate two alternatively spliced mRNAs. By diffusing into adjacent cells and binding to enzymes that contain iron, nitric oxide plays many important physiologic roles. The increase in cyclic guanosine monophosphate (cGMP) causes smooth muscle relaxation, and thus vasodilation. These findings suggest an opportunity for nitrite therapy for human diseases such as myocardial infarction, stroke, solid-organ transplantation and sickle-cell disease. The DDC encoded enzyme is also responsible for the conversion of 5-hydroxytryptophan to serotonin (see next section) and tryptophan to tryptamine.
The TPH2 gene is located on chromosome 12q21.1 and is composed of 14 exons that encode a protein (tryptophan 5-hydroxylase 2) of 490 amino acids.


The synthesis and storage of histamine by mast cells and basophils represents the greatest store (>90%) of the neurotransmitter. Several proteins, such as caveolin-1 and hsp90, interact with and affect the overall activity of eNOS. Production of NO within the brain, via nNOS, is also important for the central regulation of blood pressure.
The NO produced binds to the iron in numerous enzymes that contain the metal in their active sites. The methyl donor for this reation is S-adenosylmethionine (SAM) and the reaction is catalyzed by the enzyme guanidinoacetate N-methyltransferase. The antizyme proteins interact with ODC monomers preventing formation of functional homodimers while simultaneously altering the conformation of the monomers so that they are recognized by the proteosome. The first reaction involves the enzyme deoxyhypusine synthase which transfers the butylamine moiety from spermidine to the specific eIF-5A lysine residue.
Nitrite is also cytoprotective in the stomach, where it can prevent drug-induced gastric ulcers.
Within the brain the neurons that synthesize histamine are within the tuberomammillary nucleus of the hypothalamus. The HRH3 gene is located on chromosome 20q13.33 and is composed of 4 exons that encode a 445 amino acid protein.
Peripheral production of NO via the action of nNOS, like that produced by the action of eNOS, can effect changes in vascular tone. Examples of NO-inhibited enzymes include the Fe-S cluster-dependent activities of mitochondrial oxidative phosphorylation and ribonucleotide reductase. This latter enzyme is encoded by the GAMT gene located on chromosome 19p13.3 and is composed of 6 exons that generate two alternatively spliced mRNAs that encode isoform a (236 amino acids) and isoform b (269 amino acids).
The human genome contains five GST alpha genes, five mu genes, two omega genes, one pi gene, one sigma gene, two theta genes, and one zeta gene.
One domain is a GC-rich sequence, the other is a small functional upstream open reading frame (uORF). The second reaction involves the enzyme deoxyhypusine hydroxylase which hydroxylates the deoxyhypusine to hypusine.
Dopamine β-hydroxylase is found as both a soluble and a membrane-bound enzyme dependent upon whether or not the signal peptide from the precursor protein is present. The HRH4 gene is located on chromosome 18q11.2 and is composed of 5 exons that generate three alternatively spliced mRNAs.
Following synthesis creatine is released to the blood where is is picked up by the brain and skeletal muscle cells through the action of the SLC family member transporter, SLC6A8.
The cytosolic enzymes are functional as dimers and since the alpha and mu proteins can form functional heterodimers, the complexity of functional enzymes is greater than the number of individual subunit genes. Another significant mechanism for regulating ODC1 mRNA translation is particularly important during mitosis.
Antizyme 1 is encoded by the OAZ1 (ornithine decarboxylase antizyme 1) gene which is located on chromosome 19p13.3 and is composed of 5 exons that generate two alternatively spliced mRNAs. In addition to putrescine, the AOC1 encoded enzyme is responsible for the catabolism of histamine and other related biogenic amines. Deoxyhypusine synthase is encoded by the DHPS gene located on chromosome 19p13.2 which is composed of 13 exons that generate three alternatively spliced mRNAs, each of which encode a distinct isoform of the enzyme.
Although the general principles of nitric oxide synthesis are known, further research is necessary to determine what role it plays in causing disease. The phenylethanolamine N-methyltransferase gene (symbol: PNMT) is located on chromosome 17q12 and is composed of 5 exons that generate two alternatively spliced mRNAs, one of which is non-coding, the other encodes a protein of 282 amino acids. Neuronal NOS is expressed within smooth muscle cells of the penile corpus cavernosum and thus, NO produced by this enzyme is involved in penile erection. These effects of macrophage produced NO explain, to a large degree, the cytotoxic and cytostatic effects of NO on invading parasites as well as on certain tumor cells. Within these cells creatine is phosphorylated by creatine kinases (CK; also called creatine phosphokinase, CPK) that generate the high-energy storage compound, creatine phosphate.
Another soluble GST enzyme that is not found in the cytosol is the human GST kappa (κ, K) enzyme (encoded by the GSTK1 gene) that is localized to the peroxisomes. These two mRNAs encode antizyme 1 isoform 1 (228 amino acids) and antizyme 1 isoform 2 (226 amino acids). During the second step the enzyme oxidizes the Nω-hydroxy-L-arginine to L-citrulline and NO. Phosphorylation of eNOS enhances the flow of electrons through the reductase domain of the enzyme. The translation of the functional antizyme 1 proteins is regulated by a polyamine-regulated ribosome frameshifting mechanism.
The predominant effects of NO produced in response to eNOS activiation are vasodilation and inhibition of platelet adhesion and aggregation. The CKM gene is located on chromosome 19q13.32 and is composed of 9 exons that encode a protein of 381 amino acids. The CKB gene is located on chromosome 14q32 and is composed of 8 exons that encode a protein of 381 amino acids. Different combinations of the proteins encoded by these two genes generate tissue-specific isoforms of the functional enzymes.



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