Nos1: Difference between revisions

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Nitric oxide (NO) is produced from one of three synthases present within the body: neuronal nitric oxide synthase 1 (NOS1), inducible nitric oxide synthase 2 (NOS2), and endothelial nitric oxide synthase 3 (NOS3) (Shinkai, et. al, 2002). Specifically, NOS1 has nine different first exons that lead to multiple NOS1 transcripts with different 5’-untranslated regions (Galimberti, et. al, 2008). An advantage of having multiple first exons that can be alternatively spliced and expressed is that NOS1 can be specific and specifically regulated for different tissues (Galimberti, et. al, 2008). A disadvantage to having multiple first exons is that there is a higher possibility of mutations, which would affect NO production and thus have an effect on the second messenger cyclic guanine monophosphate (cGMP) production (Shinkai, et. al, 2002). Furthermore, because NO is an oxyradical, overproduction caused by a mutation can lead to neural tissue damage (Shinkai, et. al, 2002). Numerous pathologies may arise from neural tissue damage, and one study suggested overproduction of NO that leads to such damage is possibly an influential factor in developing schizophrenia (Shinkai, et. al, 2002).

Single nucleotide polymorphisms (SNPs) and various lengths of tandem repeats within NOS1 have been linked in other disorders of the brain such as Alzheimer’s and Parkinson’s diseases (Galimberti, et. al, 2008; Rife, et. al, 2009). Out of three identified SNPs occurring in alternative exon 1c, only the SNP G-84A has a functional effect that decreases transcription levels (Galimberti, et. al, 2008). However, various lengths of tandem repeats present in the alternative exon 1f has been shown to be a potential factor in both Alzheimer’s and Parkinson’s diseases (Galimberti, et. al, 2008; Rife, et. al, 2009). Shorter tandem TG repeats are possibly associated with the development of Alzheimer’s disease, and longer tandem TG repeats are possibly associated with the development of Parkinson’s disease (Rife, et. al, 2009). Although schizophrenia, Alzheimer’s, and Parkinson’s diseases have genetic influences, mutations in NOS1 can be a risk indicator for developing these diseases (Shinkai, et. al, 2002; Galimberti, et. al, 2008; Rife, et. al, 2009).

~~== Relevance ==~~

== Structural highlights ==

Nos exists as a homodimer. This homodimer consists of two regions. One region is an N-terminal oxygenase domain and the other is a C-terminal reductase. The N-terminal oxygenase domain is an extended beta sheet cage with binding sites for heme and pterin. ~~Nos has a~~ N-terminal catalytic domain ~~with~~ a heme active site~~. Nos 1 also has~~ a cofactor site ~~nearby~~ for tetrahydrobiopterin (H4B)~~. Nos has~~ a C-terminal reductase domain ~~containing~~ FMN, FAD and NADPH binding sites. ~~Electrons~~ are passed ~~from~~ FAD to FMN and then to the heme. This electron flow is ~~controlled~~ by the binding of CaM and ~~Ca2~~+ in the linker region between the two ~~major~~ domains. The ~~linker between~~ the ~~oxygenase~~ and ~~reductase domains~~ contains a ~~calmodulin-~~binding ~~sequence~~. ~~Nos1~~ is found ~~in neuronal tissue~~.

Nos exists as a homodimer. This homodimer consists of two regions. One region is an N-terminal oxygenase domain and the other is a C-terminal reductase. The N-terminal oxygenase domain is an extended beta sheet cage with binding sites for heme and pterin.The N-terminal catalytic domain contains a heme active site, a nearby cofactor site for tetrahydrobiopterin (H4B) and a C-terminal reductase domain that consists of FMN, FAD, and NADPH binding sites. The structure of the human nNOS heme domain contains cysteine and tryptophan. The NADPH provides electrons for catalysis. These electrons are first passed to FAD and FMN and then the heme. This electron flow is monitored by the binding of CaM and Calcium2+ in the linker region between the two heterodimer domains.

The amino acid composition of asparagine and methionine in rat neuronal NOS are conserved in human nNos. This amino acid composition influences the binding of inhibitors and makes nNos inhibitors highly selective. The structure of the human nNOS heme domain contains cysteine and tryptophan. The cysteine subunits of one region pack closely against the backbone of histidine in subunits of another region. Crystal packing interactions most likely contribute to the fully ordered N-termini in the NOS structure

There is a flexible surface loop downstream from the Zn2+ binding site. This loop in human nNOS lacks any secondary structure and appears as a random coil. This reflects the flexible nature of nNOS because it can easily adapt to local environment which involves crystal packing. This loop is found near the CaM binding site and can therefore most likely interact with it and affect electron flow.

Line 33:

Rife, T., Rasoul, B., Pullen, N., Mitchell, D., Grathwol, K., and Kurth, J. (2009) The effect of a promoter polymorphism on transcription of nitric oxide synthase 1 and its relevance to Parkinson’s disease. Journal of Neuroscience Research. 87, 2319-2325. doi:10.1005/jnr.22045

Li H, Jamal J, Plaza C, et al. Structures of human constitutive nitric oxide synthases. Acta Crystallographica Section D: Biological Crystallography. 2014;70(Pt 10):2667-2674.

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@@ Line 19: / Line 19: @@
 Nitric oxide (NO) is produced from one of three synthases present within the body: neuronal nitric oxide synthase 1 (NOS1), inducible nitric oxide synthase 2 (NOS2), and endothelial nitric oxide synthase 3 (NOS3) (Shinkai, et. al, 2002). Specifically, NOS1 has nine different first exons that lead to multiple NOS1 transcripts with different 5’-untranslated regions (Galimberti, et. al, 2008). An advantage of having multiple first exons that can be alternatively spliced and expressed is that NOS1 can be specific and specifically regulated for different tissues (Galimberti, et. al, 2008). A disadvantage to having multiple first exons is that there is a higher possibility of mutations, which would affect NO production and thus have an effect on the second messenger cyclic guanine monophosphate (cGMP) production (Shinkai, et. al, 2002). Furthermore, because NO is an oxyradical, overproduction caused by a mutation can lead to neural tissue damage (Shinkai, et. al, 2002). Numerous pathologies may arise from neural tissue damage, and one study suggested overproduction of NO that leads to such damage is possibly an influential factor in developing schizophrenia (Shinkai, et. al, 2002).
 Single nucleotide polymorphisms (SNPs) and various lengths of tandem repeats within NOS1 have been linked in other disorders of the brain such as Alzheimer’s and Parkinson’s diseases (Galimberti, et. al, 2008; Rife, et. al, 2009). Out of three identified SNPs occurring in alternative exon 1c, only the SNP G-84A has a functional effect that decreases transcription levels (Galimberti, et. al, 2008). However, various lengths of tandem repeats present in the alternative exon 1f has been shown to be a potential factor in both Alzheimer’s and Parkinson’s diseases (Galimberti, et. al, 2008; Rife, et. al, 2009). Shorter tandem TG repeats are possibly associated with the development of Alzheimer’s disease, and longer tandem TG repeats are possibly associated with the development of Parkinson’s disease (Rife, et. al, 2009). Although schizophrenia, Alzheimer’s, and Parkinson’s diseases have genetic influences, mutations in NOS1 can be a risk indicator for developing these diseases (Shinkai, et. al, 2002; Galimberti, et. al, 2008; Rife, et. al, 2009).
-== Relevance ==
 == Structural highlights ==
-Nos exists as a homodimer. This homodimer consists of two regions. One region is an N-terminal oxygenase domain and the other is a C-terminal reductase. The N-terminal oxygenase domain is an extended beta sheet cage with binding sites for heme and pterin. Nos has a N-terminal catalytic domain with a heme active site. Nos 1 also has a cofactor site nearby for tetrahydrobiopterin (H4B). Nos has a C-terminal reductase domain containing FMN, FAD and NADPH binding sites. Electrons are passed from FAD to FMN and then to the heme. This electron flow is controlled by the binding of CaM and Ca2+ in the linker region between the two major domains. The linker between the oxygenase and reductase domains contains a calmodulin-binding sequence. Nos1 is found in neuronal tissue.
+Nos exists as a homodimer. This homodimer consists of two regions. One region is an N-terminal oxygenase domain and the other is a C-terminal reductase. The N-terminal oxygenase domain is an extended beta sheet cage with binding sites for heme and pterin.The N-terminal catalytic domain contains a heme active site, a nearby cofactor site for tetrahydrobiopterin (H4B) and a C-terminal reductase domain that consists of FMN, FAD, and NADPH binding sites. The structure of the human nNOS heme domain contains cysteine and tryptophan.  The NADPH provides electrons for catalysis. These electrons are first passed to FAD and FMN and then the heme. This electron flow is monitored by the binding of CaM and Calcium2+ in the linker region between the two heterodimer domains.
+The amino acid composition of asparagine and methionine in rat neuronal NOS are conserved in human nNos. This amino acid composition influences the binding of inhibitors and makes nNos inhibitors highly selective. The structure of the human nNOS heme domain contains cysteine and tryptophan. The cysteine subunits of one region pack closely against the backbone of histidine in subunits of another region. Crystal packing interactions most likely contribute to the fully ordered N-termini in the NOS structure
+There is a flexible surface loop downstream from the Zn2+ binding site. This loop in human nNOS lacks any secondary structure and appears as a random coil. This reflects the flexible nature of nNOS because it can easily adapt to local environment which involves crystal packing. This loop is found near the CaM binding site and can therefore most likely interact with it and affect electron flow.
@@ Line 33: / Line 33: @@
 Rife, T., Rasoul, B., Pullen, N., Mitchell, D., Grathwol, K., and Kurth, J. (2009) The effect of a promoter polymorphism on transcription of nitric oxide synthase 1 and its relevance to Parkinson’s disease. Journal of Neuroscience Research. 87, 2319-2325. doi:10.1005/jnr.22045
 <references/>
+Li H, Jamal J, Plaza C, et al. Structures of human constitutive nitric oxide synthases. Acta Crystallographica Section D: Biological Crystallography. 2014;70(Pt 10):2667-2674.