Sandbox Reserved 919: Difference between revisions
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==Introduction== | ==Introduction== | ||
'''Monoglyceride Lipase''' ('''MGL''', '''MAGL''', '''MGLL''') is a 33 kDa [http://en.wikipedia.org/wiki/Protein protein] <ref name="labar"> PMID:19957260 </ref> found mostly in the cell membrane. It is a [http://en.wikipedia.org/wiki/Serine_hydrolase serine hydrolase] enzyme that exhibits an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold]. MGL plays a key role in the hydrolysis of [http://en.wikipedia.org/wiki/2-Arachidonoylglycerol 2-arachidonoylglycerol] (2-AG), an endocannabinoid produced by the the central nervous system. The α/β fold, along with a characteristic [http://en.wikipedia.org/wiki/Amphiphile amphipathic] occluded tunnel, allows 2-AG to selectively bind to the active site and be degraded into [http://en.wikipedia.org/wiki/Arachidonic_acid arachidonic acid] and [http://en.wikipedia.org/wiki/Glycerol glycerol]. Upon breakdown, glycerol leaves via a distinctive "exit tunnel" found perpendicular to the active site. 2-AG has been found to possess anti-nociceptive, immunomodulatory, anti-inflammatory and tumor-reductive character when it binds to cannabinoid receptors. <ref name="labar" /> <ref name="bert"> PMID:19962385 </ref> Due to the vast medical and therapeutic utility of 2-AG, the inhibition of MGL is a high interest target in pharmaceutical research. Furthermore, MGL has been cited as having both negative and positive effector roles in cancer pathology. | '''Monoglyceride Lipase''' ('''MGL''', '''MAGL''', '''MGLL''') is a 33 kDa [http://en.wikipedia.org/wiki/Protein protein] <ref name="labar"> PMID:19957260 </ref> found mostly in the cell membrane. It is a [http://en.wikipedia.org/wiki/Serine_hydrolase serine hydrolase] enzyme that exhibits an [http://en.wikipedia.org/wiki/Alpha/beta_hydrolase_fold α/β hydrolase fold]. MGL plays a key role in the hydrolysis of [http://en.wikipedia.org/wiki/2-Arachidonoylglycerol 2-arachidonoylglycerol] (2-AG), an endocannabinoid produced by the the central nervous system. The α/β fold, along with a characteristic [http://en.wikipedia.org/wiki/Amphiphile amphipathic] occluded tunnel, allows 2-AG to selectively bind to the active site and be degraded into [http://en.wikipedia.org/wiki/Arachidonic_acid arachidonic acid] and [http://en.wikipedia.org/wiki/Glycerol glycerol]. Upon breakdown, glycerol leaves via a distinctive "exit tunnel" found perpendicular to the active site. 2-AG has been found to possess anti-nociceptive, immunomodulatory, anti-inflammatory and tumor-reductive character when it binds to cannabinoid receptors. <ref name="labar" /> <ref name="bert"> PMID:19962385 </ref> Due to the vast medical and therapeutic utility of 2-AG, the inhibition of MGL is a high interest target in pharmaceutical research. Furthermore, MGL has been cited as having both negative and positive effector roles in cancer pathology. <ref name="nomura"> PMID:21802006 </ref> <ref name="hong"> PMID:22349814 </ref> | ||
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==Biological/Medical Relevance== | ==Biological/Medical Relevance== | ||
2-AG activates the same cannabinoid receptors (CB1 and CB2) for both [http://en.wikipedia.org/wiki/Anandamide anandamide] and the main psychoactive compound found in Cannabis sativa, [http://en.wikipedia.org/wiki/Tetrahydrocannabinol Δ9-Tetrahydrocannabinol] (THC), via [http://en.wikipedia.org/wiki/Retrograde_signaling retrograde signaling]. It is the most abundant endocannabinoid found in the brain, and it is believed to possess analgesic, anti-inflammatory, immunomodulating, neuroprotective, and hypotensive effects, as well as being capable of inhibiting growth of cancer cells in prostate and breast tissue. <ref name="labar" /><ref name="nomura" | 2-AG activates the same cannabinoid receptors (CB1 and CB2) for both [http://en.wikipedia.org/wiki/Anandamide anandamide] and the main psychoactive compound found in Cannabis sativa, [http://en.wikipedia.org/wiki/Tetrahydrocannabinol Δ9-Tetrahydrocannabinol] (THC), via [http://en.wikipedia.org/wiki/Retrograde_signaling retrograde signaling]. It is the most abundant endocannabinoid found in the brain, and it is believed to possess analgesic, anti-inflammatory, immunomodulating, neuroprotective, and hypotensive effects, as well as being capable of inhibiting growth of cancer cells in prostate and breast tissue. <ref name="labar" /> <ref name="nomura" /> | ||
Studies have shown that around 85% of 2-AG in the rat brain is metabolized by MGL, while other lipases such as [http://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase fatty acid amide hydrolase] (FAAH) process the remainder of the metabolite. <ref name="blank"> PMID:18096503 </ref> This evidence indicates that MGL is the primary enzyme for the metabolism of 2-AG in humans, making it a highly desirable target molecule for the modulation of 2-AG concentration in the body. Most MGL is found in the cell membrane, although it has been discovered in the cytosol as well. <ref name="bert" /><ref name="shalk" /><ref name="labar" /> Although the most-studied role of MGL is the degradation of 2-AG in the brain, MGL may also play a role in adipose tissue, completing the hydrolysis of triglycerides into fatty acids and glycerol, as well as working in the liver to mobilize triglycerides for secretion. <ref name="shalk" /><ref name="labar" /> | Studies have shown that around 85% of 2-AG in the rat brain is metabolized by MGL, while other lipases such as [http://en.wikipedia.org/wiki/Fatty_acid_amide_hydrolase fatty acid amide hydrolase] (FAAH) process the remainder of the metabolite. <ref name="blank"> PMID:18096503 </ref> This evidence indicates that MGL is the primary enzyme for the metabolism of 2-AG in humans, making it a highly desirable target molecule for the modulation of 2-AG concentration in the body. Most MGL is found in the cell membrane, although it has been discovered in the cytosol as well. <ref name="bert" /><ref name="shalk" /><ref name="labar" /> Although the most-studied role of MGL is the degradation of 2-AG in the brain, MGL may also play a role in adipose tissue, completing the hydrolysis of triglycerides into fatty acids and glycerol, as well as working in the liver to mobilize triglycerides for secretion. <ref name="shalk" /><ref name="labar" /> | ||
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MGL exerts a twofold influence on cancer growth; endocannabinoids such as 2-AG have been shown to have anti-tumorigenic properties <ref name="labar" /> <ref name="nomura" /> and a high fatty-acid concentration may play a role in the promotion of cancer aggressiveness and malignancy. One study showed that in aggressive breast, melanoma, ovarian, and prostate cancer cells, MGL activity was higher than in nonaggressive malignant cells. Subsequently, the creation of effective MGL inhibitors may help to treat highly aggressive cancers in addition to their proposed use as analgesics. | MGL exerts a twofold influence on cancer growth; endocannabinoids such as 2-AG have been shown to have anti-tumorigenic properties <ref name="labar" /> <ref name="nomura" /> and a high fatty-acid concentration may play a role in the promotion of cancer aggressiveness and malignancy. One study showed that in aggressive breast, melanoma, ovarian, and prostate cancer cells, MGL activity was higher than in nonaggressive malignant cells. Subsequently, the creation of effective MGL inhibitors may help to treat highly aggressive cancers in addition to their proposed use as analgesics. | ||
Contrary to this evidence, however, a recent study found that in lung, breast, ovary, stomach, and colorectal cancer, MGL expression was reduced. It was found that in addition to the previously-discussed control over the 2-AG degradation and fatty acid synthesis pathways, MGL also interacted with key phospholipids (specifically, the 3-phosphorylated phosphoinositide products of PI-3K) in the [http://en.wikipedia.org/wiki/PI3K/AKT/mTOR_pathway PI3K/Akt signaling and tumor growth pathway]. In this role, it serves as a negative effector. Indeed, decreased concentrations of MGL were found to increase [http://en.wikipedia.org/wiki/AKT Akt] phosphorylation. <ref name="hong" | Contrary to this evidence, however, a recent study found that in lung, breast, ovary, stomach, and colorectal cancer, MGL expression was reduced. It was found that in addition to the previously-discussed control over the 2-AG degradation and fatty acid synthesis pathways, MGL also interacted with key phospholipids (specifically, the 3-phosphorylated phosphoinositide products of PI-3K) in the [http://en.wikipedia.org/wiki/PI3K/AKT/mTOR_pathway PI3K/Akt signaling and tumor growth pathway]. In this role, it serves as a negative effector. Indeed, decreased concentrations of MGL were found to increase [http://en.wikipedia.org/wiki/AKT Akt] phosphorylation. <ref name= "hong" /> | ||
Further research into MGL’s role in different body tissues is necessary to more fully elucidate its complex role in cancer pathology. A specific research topic for exploration is MGL’s effect on exogenous cannabinoid medications given to cancer patients as a palliative medication. <ref name="nomura" /> | Further research into MGL’s role in different body tissues is necessary to more fully elucidate its complex role in cancer pathology. A specific research topic for exploration is MGL’s effect on exogenous cannabinoid medications given to cancer patients as a palliative medication. <ref name="nomura" /> | ||