Pathways

Mannose is a sugar monomer of the aldohexose series of carbohydrates and is a C-2 epimer of glucose. It is a key monosaccharide for protein and lipid glycosylation . The majority of mannose metabolism takes place in the cytosol. There are two routes to form mannose 6-phosphate. The first subpathway involves using beta-D-fructose 6-phosphate from glycolysis. The enzyme mannose-6-phosphate isomerase catalyzes the interconversion of beta-D-fructose 6-phosphate and D-mannose 6-phosphate. It requires a zinc ion as a cofactor. The second subpathway involves using the secreted enzyme, mannan endo-1,4-beta-mannosidase to catalyze the random hydrolysis of (1->4)-beta-D-mannosidic linkages in mannans to form D-mannose residues. These D-mannose residues are then imported into the cell cytoplasm via a sugar transport protein (a sugar/hydrogen symporter). Once inside the cell, hexokinase catalyzes the conversion of D-mannose into D-mannose 6-phosphate. Next, phosphomannomutase catalyzes the interconversion of D-mannose 6-phosphate and D-mannose 1-phosphate. However, D-mannose 1-phosphate can also be synthesized from ADP-mannose in the chloroplast via nudix hydrolase 14 and a magnesium or manganese ion cofactor. D-mannose 1-phosphate is then transported into the cytosol by a predicted D-mannose 1-phosphate transporter. Next, mannose-1-phosphate guanylyltransferase uses GTP to catalyze the conversion of D-mannose 1-phosphate into GDP-mannose. This is followed by GDP-mannose 4,6 dehydratase catalyzing the conversion of GDP-mannose into GDP-4-dehydro-6-deoxy-D-mannose. It requires NADP as a cofactor. Last, GDP-L-fucose synthase catalyzes the conversion of GDP-4-dehydro-6-deoxy-D-mannose into GDP-L-fucose.

Mannose is metabolized through the phosphorylation of mannose by a mannokinase resulting in a D-mannopyranose 6-phosphate. The latter compound is isomerized into a B-D-fructofuranose 6-phosphate which can either be incorporated into glycolysis or it can be further be metabolized into a mannose 1-phosphate through a phosphomannomutase. Mannose 1-phosphate then react with a gdp and a hydrogen ion to produce GDP-alpha-D-mannose

Mapa metabólico intregado del Homo sapiens con rutas como el ciclo de Krebs, síntesis de ácido grasos, cadena transportadora de electrones, forsforilación oxidativa etc.

Mitogen-activated protein kinases (MAPKs) are serine/threonine kinases that mediate intracellular signaling associated with a variety of cellular activities including cell proliferation, differentiation, survival, death, and transformation [1, 2]. The three main members that integrate the MAPK family in mammalian cells are stress-activated protein kinase c-Jun NH2-terminal kinase (JNK), stress-activated protein kinase 2 (SAPK2, p38), and the extracellular signal-regulated protein kinases (ERK1/2, p44/p42). ERK has a threonine-glutamic acid-tyrosine (Thr-Glu-Tyr) motif [79, 80] that plays a central role in stimulation of cell proliferation [81, 82]. The biological consequences of phosphorylation of ERK substrates include increased proliferation, differentiation, survival [83], angiogenesis [84], motility [85], and invasiveness [86]. The ERK pathway is triggered mainly by mitogens and cytokines (Figure 1), acting through receptor tyrosine kinases, G-protein-coupled receptors, and nonnuclear activated steroid hormone receptors [4, 65]. Most of the signals activating the ERK pathway are initiated through receptor-mediated activation of Ras [4] by stimulating the exchange of GDP bound to Ras for GTP [91]. Then, Ras phosphorylates Raf-1. Then, a MAPK cascade is initiated in which Raf-1 sequentially phosphorylates MEK1/2 and ERK1/2. Later, ERK1/2 translocate to the nucleus in a process that culminates in modulation of gene transcription through the activation of several transcription factors such as Ets-1 [4], ATF-2, c-Fos, c-Myc, Elk-1 [92], or NF-κB [29] (Figure 1). At the same time, ERK1/2 can also phosphorylate cytoplasmic and nuclear kinases, such as MNK1, MNK2, MPKAP-2, RSK, or MSK1 [90]. TGF-β and EGF are growth factors that can induce tumor progression by means of the ERK pathway [93–96]. Several studies showed that these factors are overexpressed in prostate cancer in comparison with normal tissue [95–98]. In different tumor cells, expression of some EGF family members such as EGF or TGF-α is associated with poor patient prognosis or resistance to chemotherapeutics [94–99]. IGF-1 and EGF stimulate intracellular signaling pathways converging at the level of ERK2 [100], which is a key kinase mediator of growth-factor-induced mitogenesis in prostate cancer cells [101]. The two major substrates of the IGF-1 receptor, insulin receptor substrate-1 [102] and Shc, are known to contribute to IGF-1-induced activation of ERK [103]. The ERK signaling pathway plays a role in several steps of tumor development [14]. In fact, some components of the Raf-MEK-ERK pathway are activated in solid tumors (such as prostate or breast cancer) and hematological malignances [104–106]. In approximately 30% of human breast cancers, mutations are found in the ERK1/2 MAPK pathway [65]. ERK1/2 and downstream ERK1/2 targets are hyperphosphorylated in a large subset of mammary tumors [107]. Mutations of K-Ras appear frequently in many cancers including those of the lung and colon [108]. Mutations in the B-Raf gene are responsible for 66% of malignant melanomas [109]. Increased expressions of Raf pathway has been associated with advanced prostate cancer, hormonal independence, metastasis, and a poor prognosis [110]. Moreover, prostate cancer cell lines isolated from patients with advanced cancer (LNCaP, PC3, DU145) expressed low levels of active Raf kinase inhibitors [105]. TNF-α acts as an ERK activator in some cases related to inflammation and cell proliferation. In this way, Ricote et al. [11] showed that ERK phosphorylation was notably increased by TNF-α in a dose-dependent manner in LNCaP cells. In prostate cancer, presence of Raf-1 and MEK1 in conjunction with elevated ERK1 and ERK2, and their phosphorylated forms, suggests that stimulation of cell proliferation could be triggered by IL-6 via the ERK pathway [104]. In fact, IL-6 expression increased in prostate cancer in comparison with normal tissue [104, 111]. Moreover, LNCaP cells which produce IL-6 show increased proliferation, at least in part, due to ERK activation [112]. Recently, a phase I clinical trial has revealed the ability of an anti-IL-6 antibody (siltuximab) to inhibit ERK1/2 phosphorylation in prostate tumors [113].

Maple syrup urine disease, also called BCKD deficiency, is a rare inborn error of metabolism (IEM) and autosomal recessive disorder caused by a defective BCKDHA, BKCDHB or DBT gene. These genes code for a protein which is vital in the breakdown of amino acids, specifically the amino acids leucine, isoleucine and valine. This disorder is characterized by a large accumulation of these amino acids in the body. Symptoms of the disorder include a distinct maple syrup smell of the urine, vomiting, lethargy, abnormal movements and delayed development. Treatment includes long-term dietary management which aims to restrict the consumption of branched-chain amino acids. It is estimated that maple syrup urine disorder affects 1 in 185,000 infants globally. This number increases significantly when looking specifically at Old World Order Mennonites, where the prevalence is 1 in 380 infants.