Neurotransmitters

I have counted the number of named cytochrome P450s as of Jan. 18, 2004. There are 1277 animal sequences, 1098 plant sequences, 207 lower eukaryote sequences and 461 bacterial sequences named. That is a total of 3043 different sequences. (Note 455 are in rice) There are many more that are not yet named, such as 150 in the white rot genome and the two Ciona genomes will have about 60-90 each. These should all be named later this year. The total is 3043 on Jan. 19, 2004. for a list of these sequences see P450 Sequence List A second list giving just one member of each subfamily has 814 entries. A third list with only one member of each family has 368 families, after allowing for CYP51 in each group and CYP97 in lower eukaryotes and plants.

A BLAST server has been set up on a RedHat Linux machine to allow blast searching of selected P450 sets. The first set available is all the Arabidopsis P450s, 273 named genes and 16 more unnamed fragments that have not been designated because I do not know if they are really different from the named genes. We plan to add more P450 sets in the next few days and weeks. Only BLASTP works now since this is a protein database. The server address is http:/132.192.64.52/blast/P450.html GO THERE NOW

THE CRYSTAL STRUCTURE OF CYP3A4, THE MOST PROLIFIC HUMAN DRUG METABOLISING P450, HAS BEEN SOLVED BY ASTEX.
SEE THE ASTEX PRESS RELEASE

A link to Comparative genomics of rice and Arabidopsis. Analysis of 727 Cytochrome P450 genes and pseudogenes from a monocot and a dicot. Plant Physiology 135, 756-772 2004

A link to Comparison of cytochrome P450 (CYP) genes from the mouse and human genomes Pharmacogenetics 14, 1-18 2004

A pdf version of Cytochrome P450 and the Individuality of Species. Archives Biochem. Biophys. 369, 1-10 1999

A pdf version of Comparison of P450s from Human and Fugu. Archives Biochem. Biophys. 409, 18-24 2003

A pdf version of Metazoan Cytochrome P450 Evolution. Comparative Biochem. Physiol. Part C 121, 15-22 1998

A pdf version of On the Topology of Vertebrate Cytochrome P450 Proteins. JBC 263, 6038-6050 1988

A link to P450 functions in plants an extensive listing with references. From the Plant Biotechnology Institute, National Research Council, Saskatoon, Saskatchewan CANADA

neurotransmitters
Neurotransmitters are small molecules that ferry information from the end of one nerve to the “beginning” of another by activating a large molecule at the far end of the synapse called a receptor. Other receptors exist presynaptically which modulate neurotransmitter release. Although there are in all likelihood hundreds of endogenous compounds that act in the CNS, it is still instructive to study the few that dominate our current understanding.
Other factors besides neurotransmitters which influence nerve function are the behavior of ion gates, G-peptides, and second messengers.

Acetylcholine was the first neurotransmitter discovered. Acetylcholine neurons convey sensory information to the brain and control muscular tension, including peristalsis. Cholinergic neurons are also present in the central nervous system (CNS).
Aspartic and glutamic acids ionize to the excitatory forms aspartate and glutamate. Aspartate and glutamate neurons occur in the CNS in hierarchical systems. These systems transport information “upward” to centers of consciousness in the cerebrum, serving an integrative function.
GABA is the most important inhibitory neurotransmitter in the CNS. It serves as a “brake” against excitatory systems such as glutamate and aspartate by gating calcium ions into the interior of nerve cells, reducing the likelihood of a positive internal action potential. Glycine is another important inhibitory amino acid. These overall neutrally-charged amino acids are inhibitory while acidic ones such as glutamate/aspartate are excitatory.
GABA, glycine, glutamate and aspartate are four examples of a class of compounds known as amino acids. These molecules contain an amine group (-NH2) and a carboxylic acid group (-COOH), hence the name. In aqueous solution the acid end of the molecule ionizes to -COO- and the amine end to -NH3+. This ionized form, known as a zwitterion, accounts for the high water solubility of amino acids. Amino acids are used by the body for many functions other than neurotransmitters, most importantly as the building blocks for proteins.

The catecholamines [epinephrine (adrenalin), norepinephrine and dopamine] control so-called adrenergic systems in the CNS. Some of these neurons radiate from the limbic system (emotional centers) and discharge neurotransmitters in a diffuse manner into the frontal cortex, i.e. into broad areas of brain tissue as opposed to delivering the chemical to specific synapses. They thus account for “global vigilance” (staying awake), mood, fight or flight response, etc. In addition they act peripherally to modulate blood pressure and other functions. These compounds are in turn controlled by peptide compounds secreted from the hypothalamus and thyroid. Just prior to waking each morning, the brain secretes ACTH (adrenocorticotropic hormone) to stimulate adrenalin release from the adrenal gland in the abdomen.
Serotonin is the primary inhibitory neurotransmitter modulating the excitatory catecholamine systems in the CNS. Serotonin neurons control memory, mood, sex drive, etc. The compound has many other functions including allergic response, and regulation of vasotension, especially in the meninges and other brain tissue. It is most highly concentrated in the gut. Melatonin, synthesized biogenically from serotonin, sets circadian rhythms, i.e. sleep cycles.
Histamine mediates allergic response and is concentrated in mast cells, whose main function is to detect trauma and release histamine and cotransmitters (leukotrienes, ATP). Another primary function of histamine is to regulate secretion of gastric acid.
Adenosine is a nucleotide, a neurotransmitter, and also a precursor to cAMP, a ubiquitous second-messenger system. Second messenger systems chemically link the activation of a post-synaptic receptor on the “beginning” (dendrite) of a neuron to the firing of voltage-dependent channels along the nerve fiber, propagating the digital information pulse. The mechanism of the IP3/DAG second-messenger system is shown on the phospholipids page.
neurotransmitter synthesis & degradation
The body synthesizes neurotransmitters from the nutrients in foods using complex catalytic molecules called enzymes. These enzymes are extremely selective “hands” which bend specific molecules or substrates and strain them, raising the (negative) energy of their bonds so they can react more efficiently at body temperature. Without these enzymes the reactions of life would proceed exceedingly slowly. After release into the synapse, the active neurotransmitters bind and detach from receptors at a given rate. Free neurotransmitter molecules must be cleaned up to return the synapse to the untriggered state. The two major mechanisms responsible for this housecleaning duty are reuptake (into presynaptic storage vesicles) and degradation.
Shown below are metabolic synthetic and degradative pathways for the major neurotransmitter systems. In many cases several pathways exist for producing a given product from a given reactant. This redundancy protects the nervous system from selective enzyme inhibition or insufficiency. Which path is taken depends on the relative activity and abundance of the given enzymes as well as the disposition of the enzymes and the relative abundance of reactants and products.
An interesting parallel exists between hormones utilized by animal and plant cells; in mny cases the same or similar hormones are used, though often for entirely different purposes. Thus tryptophan is used by animal neurons to syunthesize neurotransmitters like serotonin for, while plant cells synthesize auxin, which is used to regulate phototropic growth (i.e. the side of a plant which receives the most light secretes auxin longitudinally to cause growth in other areas, lower on the stem, towards the light).
glutamate & GABA

Just as some compounds inhibit neurotransmitter degradation by binding to and inactivating the pertinent enzymes, other compounds inhibit formation of neurotransmitters by similar mechanisms. P-chloroamphetamine and p-chlorophenylalanine are two compounds which inhibit serotonin synthesis. Alpha-methyl-m-tyrosine inhibits catecholamine synthesis.

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