Disease relevance of MSH

• A combinatorial chemistry-based diffusion assay is used to find random tripeptides that antagonize normal frog and human melanoma MSH receptors and to identify pharmacological groups responsible for receptor interaction [1].
• Our finding that the human immunodeficiency virus, among several viruses, induces ACTH and MSH production in H9 T-lymphoma cells suggests an important role of these neuropeptides in the immunosuppression characteristic of such infections [2].
• The substrate-induced conformational change of Mycobacterium tuberculosis mycothiol synthase [3].
• Mycothiol (1-D-myo-inosityl 2-(N-acetyl-L-cysteinyl)amido-2-deoxy-alpha-D-glucopyranoside, MSH or AcCys-GlcN-inositol (Ins)) is the major reducing agent in actinomycetes, including Mycobacterium tuberculosis [4].
• Data mining of the Corynebacterium glutamicum genome identified 4 genes analogous to the mshA, mshB, mshC, and mshD genes that are involved in biosynthesis of mycothiol in Mycobacterium tuberculosis and Mycobacterium smegmatis [5].

Psychiatry related information on MSH

• In both cases respiratory exchange ratio and the levels of energy expended on spontaneous physical activity were unaffected by the administration of peripheral [Nle4,D-Phe7]-alpha MSH [6].
• Neuroleptic-induced akathisia: a role for MSH peptides [7].
• The MSH/ACTH(4-9) analog Org2766 counteracts isolation-induced enhanced social behavior via the amygdala [8].
• The MSH/ACTH analog ORG 2766 in anxiety disorders [9].
• The anxiolytic effects of the MSH/ACTH analog ORG 2766 were assessed in three different groups of patients with an anxiety disorder: panic disorder, generalized anxiety and social phobia [9].

High impact information on MSH

• Because expression of, for example, the MC1 receptor is stimulated in a similar dose-dependent manner by UVR, cytokines, MSH peptides or melanin precursors, actions of the ligand peptides represent a stochastic (predictable) nonspecific response to environmental/endogenous stresses [10].
• Identification of a widely distributed receptor for ACTH/MSH peptides, the melanocortin-5 receptor (MC5-R), suggested non-steroidally mediated systemic effects of these peptides [11].
• We have identified a human homolog of the bacterial MutS and S. cerevisiae MSH proteins, called hMSH2 [12].
• This sequence confirmed the known structure of the carboxyl half of POMC and revealed the presence of a new MSH-like moiety, gamma-MSH, within the 16,000-MW amino half of the precursor (16K fragment) [13].
• 3) Recent evidence shows that neural elements in the VMN-DMN complex tonically restrain the orexigenic signals during the intermeal interval; the restraint is greatly aided by leptin's action via diminution of orexigenic (NPY) and augmentation of anorexigenic (GLP-1, alpha MSH, and CART) signals [14].

Chemical compound and disease context of MSH

• Mycothiol (MSH; 1-D-myo-inosityl-2-(N-acetyl-L-cysteinyl)amido-2-deoxy-alpha-D- glucop yranoside (AcCys-GlcN-Ins)) is a novel thiol produced at millimolar levels by mycobacteria and other actinomycetes that do not make glutathione [15].
• The structure of the ternary complex of mycothiol synthase from Mycobacterium tuberculosis with bound desacetylmycothiol and CoA was determined to 1.8 A resolution [3].
• Uptake and concentration of myo-[(14)C]inositol is rapid in Mycobacterium smegmatis and leads to production of radiolabeled inositol 1-phosphate and mycothiol [16].
• Mycothiol is comprised of N-acetylcysteine (AcCys) amide linked to 1D-myo-inosityl 2-amino-2-deoxy-alpha-D-glucopyranoside (GlcN-Ins) and is the predominant thiol found in most actinomycetes [17].
• In dogs with Cushing's syndrome due to adrenal tumors, plasma IR-ACTH, beta LPH, and beta END were decreased, and cortisol was increased, but IR-alpha MSH was normal [18].

Biological context of MSH

• Specific MSH binding sites were distributed throughout the tumor tissue, but not in associated fibrovascular elements or in neighboring nonmelanoma tissues [19].
• MSH induced up-regulation of its own receptors in three human cell lines and down-regulation in six human and two mouse melanoma cell lines [20].
• Based on the cellular measurements, MSH biosynthesis involves assembly of GlcN-Ins, ligation with Cys to produce Cys-GlcN-Ins, and acetylation of the latter to produce MSH [15].
• In recent years it has been extensively documented that peptides related to ACTH and MSH exert a neurotrophic effect on the nervous system that results in enhanced recovery of function after mechanical nerve damage [21].
• The extensive sequence identity of MshB, the deacetylase, with mycothiol S-conjugate amidase, an amide hydrolase that mediates detoxification of mycothiol S-conjugate xenobiotics, has allowed us to construct a faithful model of the catalytic domain of mycothiol S-conjugate amidase based on the structure of MshB [4].

Anatomical context of MSH

• High levels of MC5-R was found in multiple exocrine tissues, including Harderian, preputial, lacrimal, and sebaceous glands, and was also shown to be required for production and stress-regulated synthesis of porphyrins by the Harderian gland and ACTH/MSH-regulated protein secretion by the lacrimal gland [11].
• Proopiomelanocortin (POMC), the precursor for melanotropic, corticotropic, and opioid peptides such as alpha-melanocyte-stimulating hormone (alpha MSH), ACTH, and other related peptides, was originally identified as a product of the pituitary gland [22].
• These data provide first evidence that human keratinocytes produce POMC-derived peptides such as alpha MSH and ACTH [22].
• Supernatants of human normal keratinocytes and an epidermal carcinoma cell line (A431) contained significant levels of immunoreactive alpha MSH and ACTH [22].
• These data indicate that alpha- and beta MSH possess steroidogenic or growth-promoting properties, or both, for the fetal adrenal gland [23].

Associations of MSH with other chemical compounds

• TPA and retinoic acid generally down-regulated MSH receptors but had no effect on HBL cells [20].
• These genes encode several sigma factors, oxidative defence proteins, chaperones, systems to provide osmolytes, cysteine, mycothiol, and gas vesicle. sigma(B) controlled induction of itself and its two paralogues (sigma(L) and sigma(M)) in a hierarchical order of sigma(B)-->sigma(L)-->sigma(M), as revealed by S1 mapping and Western blot analyses [24].
• Plasma alpha MSH IR decreased progressively from severe preterm to fullterm neonates born by vaginal delivery (VD; P < 0.001) or cesarean section (CS) with and without prenatal distress (P < or = 0.001 in both cases). alpha MSH IR was due, in all studied conditions, to three major forms: desacetyl alpha MSH, alpha MSH, and diacetyl alpha MSH [25].
• (which use mycothiol, an inositol-containing thiol, as an intracellular redox reagent and have characteristic phosphatidylinositol-linked surface oligosaccharides) [26].
• Action potentials in gland cells of rat pituitary pars intermedia: inhibition by dopamine, an inhibitor of MSH secretion [27].

Gene context of MSH

• This work revealed a high-specificity binding state of MSH proteins for mismatch DNA that was not observed in bulk assays and allowed us to measure the affinity of MSH2-MSH6 for mismatch DNA as well as its footprint on DNA surrounding the mismatch site [28].
• Corticotropin (ACTH) and melanotropin (MSH) peptides (melanocortins) are produced not only in the pituitary but also in the brain, with highest concentrations in the arcuate nucleus of the hypothalamus and the commisural nucleus of the solitary tract [29].
• The hMSH2 (MSH for MutS homologue) protein forms a complex with a 160 kDa protein, and this heterodimer, hMutSalpha, has high affinity for a G/T mismatch [9,10] [30].
• Together, MC3-R and/or MC-4R mRNA are found in every nucleus reported to bind MSH in the adult rat brain and define neuronal circuitry known to be involved in the control of diverse neuroendocrine and autonomic functions [31].
• In conclusion, alpha MSH antagonizes CRH inhibition of LH secretion [32].

Analytical, diagnostic and therapeutic context of MSH

• Upon immuneprecipitation and size-exclusion chromatography, keratinocyte-derived alpha MSH exhibited a molecular mass of approximately 1 kD and was biologically active as demonstrated in a tyrosinase bioassay [22].
• Radioimmunoassay for MSH of supernatant fluids from granulocytes incubated with ACTH demonstrated a time-dependent increase in MSH [2].
• The production of alpha-melanotropin (alpha-N-acetyl-ACTH(1-13)NH2 (alpha MSH) in rat intermediate pituitary was investigated using reverse phase high performance liquid chromatography, immunoassays, and biosynthetic labeling [33].
• Immunoprecipitation analysis of pulse-labeled tyrosinase from control and MSH-treated cultures (48-h exposure) has demonstrated that MSH stimulates tyrosinase synthesis by approximately 4-fold, a level of induction which does not correspond to the observed 14-fold increase in enzyme activity [34].
• When immunotitration curves were developed from cell extracts of control and MSH-treated cultures using immunoprecipitation and competitive enzyme-linked immunosorbent assay protocols, evidence for the presence of immunologically active but catalytically less active enzyme in untreated melanoma cell cultures was demonstrated [34].

References