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Signal path
Autophagy | 自噬

Autophagy is an intracellular degradation system that delivers cytoplasmic constituents to the lysosome. Autophagy plays a wide variety of physiological and pathophysiological roles. Different selective forms of autophagy have been identified and characterized, leading to the specific degradation of organelles or pathogens. These selective pathways include the autophagic degradation of mitochondria (mitophagy), peroxisomes (pexophagy), endoplasmic reticulum (reticulophagy or ER-phagy), ribosomes (ribophagy), protein aggregates (aggrephagy), lipid droplets (lipophagy), spermatozoon-inherited organelles following fertilization (allophagy), secretory granules within pancreatic cells (zymophagy), or intracellular pathogens (xenophagy).

Autophagy consists of several sequential steps--sequestration, transport to lysosomes, degradation, and utilization of degradation products--and each step may exert different function. Autophagy signal transduction are mainly regulated by autophagy-related genes/proteins, Atgs. ATGs have unveiled much of the machinery of autophagosome formation. Furthermore, different non-ATG proteins are involved in the regulation and process of autophagy, e.g., mTOR, AMPK, AKT, AMBRA1, BCL2, DFCP1, or VPS34.

Autophagy and its dysregulation have been implicated in different human diseases or processes, such as cancer, neurodegeneration, immunity, or aging. Plenty of drugs and natural products are involved in autophagy modulation, either inducing or inhibiting autophagy, through multiple signaling pathways. Small molecules that can regulate autophagy seem to have great potential to modulate the clinical course of neurodegenerative diseases or promote chemotherapeutic response in tumor models. Besides, several clinical drugs and compounds in diabetes are also found to involve regulation of autophagy.

 

参考文献:

[1]. Glick D, et al. J Pathol. 2010 May;221(1):3-12.

[2]. Mizushima N. Genes Dev. 2007 Nov 15;21(22):2861-73.

[3]. Wesselborg S, et al. Cell Mol Life Sci. 2015 Dec;72(24):4721-57.

[4]. Zhang XW, et al. J Asian Nat Prod Res. 2017 Apr;19(4):314-319.

 

Immunology/Inflammation | 免疫及炎症
Immunology/Inflammation——Arginase Immunology/Inflammation——Aryl Hydrocarbon Receptor Immunology/Inflammation——CCR Immunology/Inflammation——CD73 Immunology/Inflammation——Complement System Immunology/Inflammation——COX Immunology/Inflammation——CXCR Immunology/Inflammation——Cyclic GMP-AMP Synthase Immunology/Inflammation——FKBP Immunology/Inflammation——FLAP Immunology/Inflammation——Galectin Immunology/Inflammation——Histamine Receptor Immunology/Inflammation——IFNAR Immunology/Inflammation——Interleukin Related Immunology/Inflammation——IRAK Immunology/Inflammation——MyD88 Immunology/Inflammation——NO Synthase Immunology/Inflammation——NOD-like Receptor (NLR) Immunology/Inflammation——PD-1/PD-L1 Immunology/Inflammation——PGE synthase Immunology/Inflammation——Pyroptosis Immunology/Inflammation——Reactive Oxygen Species Immunology/Inflammation——Salt-inducible Kinase (SIK) Immunology/Inflammation——SphK Immunology/Inflammation——STING Immunology/Inflammation——Thrombopoietin Receptor Immunology/Inflammation——Toll-like Receptor (TLR) Immunology/Inflammation——FAP Immunology/Inflammation——AIM2 Immunology/Inflammation——AP-1 Immunology/Inflammation——ALCAM/CD166 Immunology/Inflammation——CD2 Immunology/Inflammation——CD3 Immunology/Inflammation——CD6 Immunology/Inflammation——CD19 Immunology/Inflammation——CD20 Immunology/Inflammation——CD22 Immunology/Inflammation——CD28 Immunology/Inflammation——CD38 Immunology/Inflammation——CX3CR1 Immunology/Inflammation——CTLA-4 Immunology/Inflammation——DOCK Immunology/Inflammation——Glycoprotein VI Immunology/Inflammation——Glucocorticoid Receptor Immunology/Inflammation——Mucin Immunology/Inflammation——Mesothelin Immunology/Inflammation——Macrophage migration inhibitory factor (MIF) Immunology/Inflammation——Nuclear Factor of activated T Cells (NFAT) Immunology/Inflammation——PSMA Immunology/Inflammation——SOD Immunology/Inflammation——Tim3 Immunology/Inflammation——Immunology/Inflammation related

The immune system has evolved to survey and respond appropriately to the universe of foreign pathogens, deploying an intricate repertoire of mechanisms that keep responses to host tissues in check. The immune system is typically divided into two categories--innate and adaptive. Innate immunity refers to nonspecific defense mechanisms that come into play immediately or within hours of an antigen's appearance in the body. Adaptive immunity refers to antigen-specific immune response. The antigen first must be processed and recognized, and then the adaptive immune system creates an army of immune cells specifically designed to attack that antigen. For the adaptive immune system, specificity and sensitivity are provided by a large repertoire of antigen T-cell receptors (TCRs) constructed in their extracellular domain to recognize antigenic peptide fragments restricted and presented by histocompatibility complex molecules, and coupled through intracellular domains to signal transduction modules that serve to transmit environmental cues inside the cell.

Inflammation is triggered when innate immune cells detect infection or tissue injury. Pattern recognition receptors (PRRs) respond to pathogen-associated molecular patterns (PAMPs) or host-derived damage-associated molecular patterns (DAMPs) by triggering activation of NF-κB, AP1, CREB, c/EBP, and IRF transcription factors. Induction of genes encoding enzymes, chemokines, cytokines, adhesion molecules, and regulators of the extracellular matrix promotes the recruitment and activation of leukocytes. Besides resolving infection and injury, chronic inflammation is a risk factor for cancer.

Immunity has a major impact on inflammatory diseases and cancer, and biologics targeting immune cells and their factors. Immunosuppressant drugs suppress, or reduce, the strength of the body’s immune system, and have been used in the treatment of organ transplantation or autoimmunine diseases. Immunomodulator drugs have contributed to the significant improvement against cancer and other related diseases.

 

参考文献:

[1] Sakaguchi S, et al. Immunol Cell Biol. 2012 Mar;90(3):277-87. doi: 10.1038/icb.2012.4.

[2] Newton K, et al. Cold Spring Harb Perspect Biol. 2012 Mar; 4(3): a006049.

[3] Bartneck M. Macromol Biosci. 2017 Apr 6. doi: 10.1002/mabi.201700021.

 

Neuronal Signaling | 神经信号通路
Neuronal Signaling——5-HT Receptor Neuronal Signaling——AChE Neuronal Signaling——Adenosine Kinase Neuronal Signaling——Adrenergic Receptor Neuronal Signaling——Amyloid-β Neuronal Signaling——Beta-secretase Neuronal Signaling——Calcium Channel Neuronal Signaling——CaMK Neuronal Signaling——Cannabinoid Receptor Neuronal Signaling——Dopamine Transporter Neuronal Signaling——CGRP Receptor Neuronal Signaling——Cholecystokinin Receptor Neuronal Signaling——COMT Neuronal Signaling——Dopamine Receptor Neuronal Signaling——FAAH Neuronal Signaling——GABA Receptor Neuronal Signaling——GlyT Neuronal Signaling——GPR119 Neuronal Signaling——GPR139 Neuronal Signaling——GPR55 Neuronal Signaling——Histamine Receptor Neuronal Signaling——iGluR Neuronal Signaling——Imidazoline Receptor Neuronal Signaling——mAChR Neuronal Signaling——MCHR1 (GPR24) Neuronal Signaling——Melanocortin Receptor Neuronal Signaling——Melatonin Receptor Neuronal Signaling——mGluR Neuronal Signaling——Monoamine Oxidase Neuronal Signaling——nAChR Neuronal Signaling——Neurokinin Receptor Neuronal Signaling——Neuropeptide Y Receptor Neuronal Signaling——Neurotensin Receptor Neuronal Signaling——Notch Neuronal Signaling——Opioid Receptor Neuronal Signaling——Orexin Receptor (OX Receptor) Neuronal Signaling——Serotonin Transporter Neuronal Signaling——Sigma Receptor Neuronal Signaling——Somatostatin Receptor Neuronal Signaling——Trk Receptor Neuronal Signaling——TRP Channel Neuronal Signaling——γ-secretase Neuronal Signaling——Cholinesterase (ChE) Neuronal Signaling——AAK1 Neuronal Signaling——α-synuclein Neuronal Signaling——Glucosylceramide Synthase (GCS) Neuronal Signaling——Huntingtin Neuronal Signaling——Tau Protein Neuronal Signaling——Transthyretin (TTR) Neuronal Signaling——AChR

Neuronal Signaling is involved in the regulation of the mechanics of the central nervous system such as its structure, function, genetics and physiology as well as how this can be applied to understand diseases of the nervous system. Every information processing system in the CNS is composed of neurons and glia, neurons have evolved unique capabilities for intracellular signaling (communication within the cell) and intercellular signaling (communication between cells).

G protein-coupled receptors (GPCRs), including 5-HT receptor, histamine receptor, opioid receptor, and etc, are the largest class of sensory proteins and are important therapeutic targets in Neuronal Signaling. GPCRs are activated by diverse stimuli, including light, enzymatic processing of their N-termini, and binding of proteins, peptides, or small molecules such as neurotransmitters, and regulate neuronal excitability by indirectly modulating the function of voltage-gated channels, such as voltage-gated calcium channel and transient receptor potential (TRP) ion channels. Besides, Notch signaling, such as β- and γ-secretase, also plays multiple roles in the development of the CNS including regulating neural stem cell (NSC) proliferation, survival, self-renewal and differentiation.

GPCR dysfunction caused by receptor mutations and environmental challenges contributes to many neurological diseases. Notch signaling in neurons, glia, and NSCs is also involved in pathological changes that occur in disorders such as stroke, Alzheimer's disease and CNS tumors. Thus, targeting Neuronal Signaling, such as notch signaling and GPCRs, can be used as therapeutic interventions for several different CNS disorders.

 

参考文献:

[1] Lathia JD, et al. J Neurochem. 2008 Dec;107(6):1471-81.

[2] Palczewski K, et al. Annu Rev Neurosci. 2013 Jul 8;36:139-64.

[3] Geppetti P, et al. Neuron. 2015 Nov 18;88(4):635-49.

 

Protein Tyrosine Kinase/RTK | 蛋白酪氨酸激酶

Protein-tyrosine kinases (PTKs) catalyze the transfer of the γ-phosphate of ATP to tyrosine residues of protein substrates, are critical components of signaling pathways that control cellular proliferation and differentiation. Two classes of PTKs are present in cells: the transmembrane receptor PTKs and the nonreceptor PTKs.

The RTK family includes the receptors for insulin and for many growth factors, such as EGF, FGF, PDGF, VEGF, and NGF. RTKs are transmembrane glycoproteins that are activated by the binding of their ligands, and they transduce the extracellular signal to the cytoplasm by phosphorylating tyrosine residues on the receptors themselves (autophosphorylation) and on downstream signaling proteins. RTKs activate numerous signaling pathways within cells, leading to cell proliferation, differentiation, migration, or metabolic changes. In addition, nonreceptor tyrosine kinases (NRTKs), which include Src, JAKs, and Abl, among others, are integral components of the signaling cascades triggered by RTKs and by other cell surface receptors such as GPCRs and receptors of the immune system. NRTKs are critical components in the regulation of the immune system.

RTKs and NRTKs have been implicated in the progression of diseases such as cancer, diabetic retinopathy, atherosclerosis, and psoriasis. Protein kinases, including RTKs, are one of the most frequently mutated gene families implicated in cancer, which has prompted numerous studies on their role in cancer pathogenesis. There are four main mechanisms of RTK dysregulation in human cancers: genomic rearrangements, autocrine activation, overexpression and gain- or loss-of-function mutations. Currently, there are several clinically available small molecule inhibitors and monoclonal antibodies against specific RTKs.

 

 

TGF-beta/Smad | TGF-beta/Smad 信号通路

The TGF-β superfamily comprises TGF-βs, bone morphogenetic proteins (BMPs), activins and related proteins. These proteins were identified mainly through their roles in development; they regulate the establishment of the body plan and tissue differentiation through their effects on cell proliferation, differentiation and migration. There are eight vertebrate Smads: Smad1 to Smad8. Smad2 and Smad3 are activated through carboxy-terminal phosphorylation by the TGF-b and activin receptors TbRI and ActRIB, whereas Smad1, Smad5 and Smad8 are activated by ALK-1, ALK-2, BMP-RIA/ALK-3 and BMP-RIB/ALK-6 in response to BMP1–4 or other ligands.

TGF-β binds two receptor types, the TGF-β type I and type II receptors (TβRI and TβRII, respectively) to form the active signaling complex. The TβRII activates TβRI kinase activity by phosphorylating the TβRI, which then transmits the signal intracellularly by phosphorylating the Smad transcription factors. The Smads constitutively shuttle between the cytoplasm and nucleus, but signaling causes the Smads to accumulate predominantly in the nucleus where they bind DNA and other transcriptional machinery to regulate the expression of target genes. TGF-β also involves in the regulations of PI3K and MAPK signaling pathways.

Abnormalities of the TGF-beta receptors and SMADs have been detected in various tumors, including colorectal cancers and pancreatic cancers. In addition, TGF-β/BMP signaling is also involved in osteoblast differentiation, chondrocyte differentiation, skeletal development, cartilage formation, bone formation, bone homeostasis, and related human bone diseases caused by the disruption ofTGF-β/BMP signaling.

 

参考文献:

[1] Derynck R, et al. Nature. 2003 Oct 9;425(6958):577-84.

[2] Clarke DC, et al. Trends Cell Biol. 2008 Sep;18(9):430-42.

[3] Wu M, et al. Bone Res. 2016 Apr 26;4:16009.

 

MAPK/ERK Pathway | MAPK/ERK 信号通路

MAPK families play an important role in complex cellular programs like proliferation, differentiation, development, transformation, and apoptosis. In mammalian cells, three MAPK families have been clearly characterized: namely classical MAPK (ERK), C-Jun N-terminal kinse/ stress-activated protein kinase (JNK/SAPK) and p38 kinase. Each MAPK-related cascade consists of no fewer than three enzymes that are activated in series: a MAPK kinase kinase (MAPKKK), a MAPK kinase (MAPKK) and a MAP kinase (MAPK).

The MAPK pathways are activated by diverse extracellular and intracellular stimuli including peptide growth factors, cytokines, hormones, and various cellular stressors. In the ERK signaling pathway, ERK1/2 is activated by MEK1/2, which is activated by Raf. Raf is activated by the Ras GTPase, whose activation is induced by RTKs such as the epidermal growth factor receptor. The JNK and p38 MAPK signaling pathways are activated by various types of cellular stress. The JNK pathway consists of JNK, a MAP2K such as MKK4 (SEK1) or MKK7, and a MAP3K such as ASK1, TAK1, MEKK1, or MLK3. In the p38 pathway, p38 is activated by MKK3 or MKK6, and these MAP2Ks are activated by the same MAP3Ks that function in the JNK pathway.

MAPK signaling pathways has been implicated in the development of many human diseases including Alzheimer's disease (AD), Parkinson's disease (PD), amyotrophic lateral sclerosis (ALS) and various types of cancers. Therefore, the development of small molecule drugs that selectively inhibit individual components of MAPK signaling pathways is a key therapeutic strategy for cancer and neurodegenerative disorders.

 

参考文献:

[1] Zhang W, et al. Cell Research (2002) 12, 9-18.

[2] Kim EK, et al. Biochim Biophys Acta. 2010 Apr;1802(4):396-405.

[3] Kim EK, et al. Arch Toxicol. 2015 Jun;89(6):867-82.

 

JAK/STAT Signaling | JAK/STAT 信号通路

The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) pathway is central to signaling by cytokine receptors, a superfamily of more than 30 transmembrane proteins that recognize specific cytokines, and is critical in blood formation and immune response. Canonical JAK/STAT signaling begins with the association of cytokines and their corresponding transmembrane receptors. Activated JAKs then phosphorylate latent STAT monomers, leading to dimerization, nuclear translocation, and DNA binding. In mammals, there are four JAKs (JAK1, JAK2, JAK3, TYK2) and seven STATs (STAT1, STAT2, STAT3, STAT4, STAT5a, STAT5b, STAT6).

JAKs are an integral component of the receptor subunit with very little release or exchange into the cytoplasm and as such are located primarily at the plasma membrane. STAT has seven conserved features: an N-terminal domain (NT), a coiled-coil domain (CC), a central DNA-binding domain (DBD), a linker region, an SH2 domain followed by a single conserved tyrosine residue, and a C-terminal transactivation domain (TAD). JAK phosphorylation of the STAT proteins then results in a spatial reorganisation of the dimer complex, and translocates to the nucleus. Once in the nucleus, STAT dimmers are stabilised by NT:NT interactions and bind cooperatively to tandem sequence elements within promoter regions to activate the transcription of specific gene subsets.

Aberrant activation of the JAK/STAT pathway has been reported in a variety of diseases, including inflammatory conditions, hematologic malignancies, and solid tumors. More recently, human myeloproliferative neoplasms are discovered to be associated with a unique acquired somatic mutation in JAK2 (JAK2 V617F), rare exon 12 JAK2 mutations, or thrombopoietin receptor mutations that constitutively activate wild-type JAK2. As a result, several drug companies have begun to develop therapeutics that inhibit the function of JAK tyrosine kinases. Currently, several JAK-targeting drugs have been used in the clinic for treating diseases including rheumatoid arthritis and myeloproliferative.

 

参考文献:

[1] Kiu H, et al. Growth Factors. 2012 Apr;30(2):88-106.

[2] Quintás-Cardama A, et al. Clin Cancer Res. 2013 Apr 15;19(8):1933-40.

[3] Villarino AV, et al. J Immunol. 2015 Jan 1;194(1):21-7.

[4] Vainchenker W, et al. Oncogene. 2013 May 23;32(21):2601-13.

 

GPCR/G Protein | G 蛋白偶联受体/G 蛋白
GPCR/G Protein——5-HT Receptor GPCR/G Protein——Adenosine Receptor GPCR/G Protein——Adenylate Cyclase GPCR/G Protein——Adiponectin Receptor GPCR/G Protein——Adrenergic Receptor GPCR/G Protein——Angiotensin Receptor GPCR/G Protein——Bombesin Receptor GPCR/G Protein——Bradykinin Receptor GPCR/G Protein——Cannabinoid Receptor GPCR/G Protein——CaSR GPCR/G Protein——CCR GPCR/G Protein——CGRP Receptor GPCR/G Protein——Cholecystokinin Receptor GPCR/G Protein——CRFR GPCR/G Protein——CXCR GPCR/G Protein——Dopamine Receptor GPCR/G Protein——EBI2/GPR183 GPCR/G Protein——Endothelin Receptor GPCR/G Protein——GHSR GPCR/G Protein——Glucagon Receptor GPCR/G Protein——Glucocorticoid Receptor GPCR/G Protein——GnRH Receptor GPCR/G Protein——GPCR19 GPCR/G Protein——GPR109A GPCR/G Protein——GPR119 GPCR/G Protein——GPR120 GPCR/G Protein——GPR139 GPCR/G Protein——GPR40 GPCR/G Protein——GPR55 GPCR/G Protein——GPR84 GPCR/G Protein——Guanylate Cyclase GPCR/G Protein——Histamine Receptor GPCR/G Protein——Imidazoline Receptor GPCR/G Protein——Leukotriene Receptor GPCR/G Protein——LPL Receptor GPCR/G Protein——mAChR GPCR/G Protein——MCHR1 (GPR24) GPCR/G Protein——Melanocortin Receptor GPCR/G Protein——Melatonin Receptor GPCR/G Protein——mGluR GPCR/G Protein——Motilin Receptor GPCR/G Protein——Neurokinin Receptor GPCR/G Protein——Neuropeptide Y Receptor GPCR/G Protein——Neurotensin Receptor GPCR/G Protein——Opioid Receptor GPCR/G Protein——Orexin Receptor (OX Receptor) GPCR/G Protein——Oxytocin Receptor GPCR/G Protein——P2Y Receptor GPCR/G Protein——Prostaglandin Receptor GPCR/G Protein——Protease-Activated Receptor (PAR) GPCR/G Protein——Ras GPCR/G Protein——RGS Protein GPCR/G Protein——Sigma Receptor GPCR/G Protein——Somatostatin Receptor GPCR/G Protein——TSH Receptor GPCR/G Protein——Urotensin Receptor GPCR/G Protein——Vasopressin Receptor GPCR/G Protein——Apelin Receptor (APJ) GPCR/G Protein——Amylin Receptor GPCR/G Protein——GCGR GPCR/G Protein——GLP Receptor GPCR/G Protein——PTHR GPCR/G Protein——Secretin Receptor GPCR/G Protein——Arrestin GPCR/G Protein——G Protein-coupled Receptor Kinase (GRK) GPCR/G Protein——Formyl Peptide Receptor (FPR) GPCR/G Protein——Free Fatty Acid Receptor GPCR/G Protein——GPR4 GPCR/G Protein——GPR6 GPCR/G Protein——GPR68 GPCR/G Protein——GPR88 GPCR/G Protein——GPR35 GPCR/G Protein——GPR52 GPCR/G Protein——GPR171 GPCR/G Protein——Kisspeptin Receptor GPCR/G Protein——Succinate Receptor 1 GPCR/G Protein——G protein-coupled Bile Acid Receptor 1 GPCR/G Protein——Hydroxycarboxylic Acid Receptor (HCAR) GPCR/G Protein——Hydroxycarboxylic Acid Receptor (HCAR) GPCR/G Protein——Platelet-activating Factor Receptor (PAFR) GPCR/G Protein——Trace Amine-associated Receptor (TAAR) GPCR/G Protein——Mas-related G-protein-coupled Receptor (MRGPR) GPCR/G Protein——GPR

G Protein Coupled Receptors (GPCRs) perceive many extracellular signals and transduce them to heterotrimeric G proteins, which further transduce these signals intracellular to appropriate downstream effectors and thereby play an important role in various signaling pathways. G proteins are specialized proteins with the ability to bind the nucleotides guanosine triphosphate (GTP) and guanosine diphosphate (GDP). In unstimulated cells, the state of G alpha is defined by its interaction with GDP, G beta-gamma, and a GPCR. Upon receptor stimulation by a ligand, G alpha dissociates from the receptor and G beta-gamma, and GTP is exchanged for the bound GDP, which leads to G alpha activation. G alpha then goes on to activate other molecules in the cell. These effects include activating the MAPK and PI3K pathways, as well as inhibition of the Na+/H+ exchanger in the plasma membrane, and the lowering of intracellular Ca2+ levels.

Most human GPCRs can be grouped into five main families named; Glutamate, Rhodopsin, Adhesion, Frizzled/Taste2, and Secretin, forming the GRAFS classification system.

A series of studies showed that aberrant GPCR Signaling including those for GPCR-PCa, PSGR2, CaSR, GPR30, and GPR39 are associated with tumorigenesis or metastasis, thus interfering with these receptors and their downstream targets might provide an opportunity for the development of new strategies for cancer diagnosis, prevention and treatment. At present, modulators of GPCRs form a key area for the pharmaceutical industry, representing approximately 27% of all FDA-approved drugs.

 

参考文献:

[1] Moreira IS. Biochim Biophys Acta. 2014 Jan;1840(1):16-33.

[2] Tuteja N. Plant Signal Behav. 2009 Oct;4(10):942-7.

[3] Williams C, et al. Methods Mol Biol. 2009;552:39-50.

[4] Schiöth HB, et al. Gen Comp Endocrinol. 2005 May 15;142(1-2):94-101.

[5] Wu J, et al. Cancer Genomics Proteomics. 2012 Jan;9(1):37-50.

Cell Cycle/DNA Damage | 细胞周期/DNA 损伤
Cell Cycle/DNA Damage——Antifolate Cell Cycle/DNA Damage——APC Cell Cycle/DNA Damage——ATM/ATR Cell Cycle/DNA Damage——Aurora Kinase Cell Cycle/DNA Damage——Casein Kinase Cell Cycle/DNA Damage——CDK Cell Cycle/DNA Damage——Checkpoint Kinase (Chk) Cell Cycle/DNA Damage——CRISPR/Cas9 Cell Cycle/DNA Damage——Deubiquitinase Cell Cycle/DNA Damage——DNA Alkylator/Crosslinker Cell Cycle/DNA Damage——DNA-PK Cell Cycle/DNA Damage——DNA/RNA Synthesis Cell Cycle/DNA Damage——Eukaryotic Initiation Factor (eIF) Cell Cycle/DNA Damage——G-quadruplex Cell Cycle/DNA Damage——Haspin Kinase Cell Cycle/DNA Damage——HDAC Cell Cycle/DNA Damage——HSP Cell Cycle/DNA Damage——IRE1 Cell Cycle/DNA Damage——Kinesin Cell Cycle/DNA Damage——LIM Kinase (LIMK) Cell Cycle/DNA Damage——Microtubule/Tubulin Cell Cycle/DNA Damage——Mps1 Cell Cycle/DNA Damage——Nucleoside Antimetabolite/Analog Cell Cycle/DNA Damage——p97 Cell Cycle/DNA Damage——PAK Cell Cycle/DNA Damage——PARP Cell Cycle/DNA Damage——PERK Cell Cycle/DNA Damage——Polo-like Kinase (PLK) Cell Cycle/DNA Damage——PPAR Cell Cycle/DNA Damage——RAD51 Cell Cycle/DNA Damage——ROCK Cell Cycle/DNA Damage——Sirtuin Cell Cycle/DNA Damage——SRPK Cell Cycle/DNA Damage——Telomerase Cell Cycle/DNA Damage——TOPK Cell Cycle/DNA Damage——Topoisomerase Cell Cycle/DNA Damage——Wee1 Cell Cycle/DNA Damage—— Cyclin G-associated Kinase (GAK) Cell Cycle/DNA Damage——Early 2 Factor (E2F) Cell Cycle/DNA Damage——DNA Stain Cell Cycle/DNA Damage——ATF6 Cell Cycle/DNA Damage——PDI

Cell Cycle includes many processes necessary for successful self-replication, and consists of DNA synthesis (S) and mitosis (M) phases separated by gap phases in the order G1–S–G2–M. S phase and M phase are usually separated by gap phases called G1 and G2, when cell-cycle progression can be regulated by various intracellular and extracellular signals. In order to move from one phase of its life cycle to the next, a cell must pass through numerous checkpoints. At each checkpoint, specialized proteins determine whether the necessary conditions exist. Progression through G1 phase is controlled by pRB proteins, and phosphorylation of pRB proteins by CDKs releases E2F factors, promoting the transition to S phase. The G2/M transition that commits cells to division is a default consequence of initiating the cell cycle at the G1/S transition, many proteins, such Wee1, PLK1 and cdc25, is involved the regulation of this process. The best-understood checkpoints are those activated by DNA damage and problems with DNA replication.

DNA damage response (DDR) is a series of regulatory events including DNA damage, cell-cycle arrest, regulation of DNA replication, and repair or bypass of DNA damage to ensure the maintenance of genomic stability and cell viability. Genome instability arises if cells initiate mitosis when chromosomes are only partially replicated or are damaged by a double-strand DNA break (DSB). To prevent cells with damaged DNA from entering mitosis, ATR inhibits cyclin B/Cdk1 activation by stimulating the Cdk1 inhibitory kinase Wee1 and inhibiting Cdc25C via Chk1, besides, ATM and ATR also initiate DNA repair by phosphorylating several other substrates.

In cancer cells, the cell cycle regulators as well as other elements of the DDR pathway have been found to protect tumor cells from different stresses and to promote tumor progression. Thus, cell cycle proteins that directly regulate cell cycle progression (such as CDKs), as well as checkpoint kinases, Aurora kinases and PLKs, are promising targets in cancer therapy.

 

参考文献:

[1] Rhind N, et al. Cold Spring Harb Perspect Biol. 2012 Oct; 4(10): a005942.

[2] Duronio RJ, et al. Cold Spring Harb Perspect Biol. 2013 Mar; 5(3): a008904.

[3] Liu W, et al. Mol Cancer. 2017 Mar 14;16(1):60.

[4] Ghelli Luserna di Rora' A, et al. J Hematol Oncol. 2017 Mar 29;10(1):77.

 

Apoptosis | 凋亡

Cell apoptosis, sometimes called programmed cell death, is a cellular self-destruction method to remove old and damaged cells during development and aging to protect cells from external disturbances and maintain homeostasis. Apoptosis also occurs as a defense mechanism such as in immune reactions or when cells are damaged by disease or noxious agents.

Apoptosis is controlled by many genes and involves two fundamental pathways: the extrinsic pathway, which transmits death signals by the death receptor (DR), and the intrinsic or mitochondrial pathway. The extrinsic apoptotic pathway is activated by the binding of the death ligand to DRs, including FasL, TNF-α, and TRAIL, on the plasma membrane. The DR, adaptor protein (FADD), and associated apoptosis signaling molecule (caspase-8) form the death-inducing signaling complex (DISC), thus leading to the activation of the effector caspase cascade (caspase-3, -6, and -7). The mitochondria-mediated intrinsic apoptosis pathway is regulated by Bcl-2 family proteins, including proapoptotic (Bid, Bax, Bak) and antiapoptotic proteins (Bcl-2, Bcl-xL).

Abnormalities in cell apoptosis can be a significant component of diseases such as cancer, autoimmune lymphoproliferative syndrome, AIDS, ischemia, and neurode-generative diseases. These diseases may benefit from artificially inhibiting or activating apoptosis. A short list of potential methods of anti-apoptotic therapy includes stimulation of the IAP (inhibitors of apoptosis proteins) family of proteins, caspase inhibition, PARP (poly [ADP-ribose] polymerase) inhibition, stimulation of the PKB/Akt (protein kinase B) pathway, and inhibition of Bcl-2 proteins.

Ferroptosis and necroptosis are recently recognized forms of regulated cell death that differs considerably from apoptosis. Misregulated ferroptosis or necroptosis have also been implicated in multiple physiological and pathological processes, including cancer cell death, neurotoxicity, neurodegenerative diseases, etc.

 

参考文献:

[1] Susan Elmore. Toxicol Pathol. 2007; 35(4): 495–516.

[2] Cao L, et al. J Cell Death. 2016 Dec 29;9:19-29.

[3] Dasgupta A, et al. Int J Mol Sci. 2017 Jan; 18(1): 23.

[4] Xie Y, et al. Cell Death Differ. 2016 Mar;23(3):369-79.

ADC Related | 抗体偶联药物相关

The antibody-drug conjugate (ADC), a humanized or human monoclonal antibody conjugated with highly cytotoxic small molecules (payloads) through chemical linkers, is a novel therapeutic format and has great potential to make a paradigm shift in cancer chemotherapy. The three components of the ADC together give rise to a powerful oncolytic agent capable of delivering normally intolerable cytotoxins directly to cancer cells, which then internalize and release the cell-destroying drugs. At present, two ADCs, Adcetris and Kadcyla, have received regulatory approval with >40 others in clinical development.

ADCs are administered intravenously in order to prevent the mAb from being destroyed by gastric acids and proteolytic enzymes. The mAb component of the ADC enables it to circulate in the bloodstream until it finds and binds to tumor-specific cell surface antigens present on target cancer cells. Linker chemistry is an important determinant of the safety, specificity, potency and activity of ADCs. Linkers are designed to be stable in the blood stream (to conform to the increased circulation time of mAbs) and labile at the cancer site to allow rapid release of the cytotoxic drug. First generation ADCs made use of early cytotoxins such as the anthracycline, doxorubicin or the anti-metabolite/antifolate agent, methotrexate. Current cytotoxins have far greater potency and can be divided into three main groups: auristatins, maytansines and calicheamicins.

The development of site-specific conjugation methodologies for constructing homogeneous ADCs is an especially promising path to improving ADC design, which will open the way for novel cancer therapeutics.

 

参考文献:

[1] Tsuchikama K, et al. Protein Cell. 2016 Oct 14. DOI:10.1007/s13238-016-0323-0.

[2] Peters C, et al. Biosci Rep. 2015 Jun 12;35(4). pii: e00225. doi: 10.1042/BSR20150089.

NF-κB | NF-κB 信号通路

Rel/NF-κB proteins are dimeric, DNA sequence-specific transcription factors that coordinate inflammatory responses; innate and adaptive immunity; and cellular differentiation, proliferation, and survival in almost all multicellular organisms. In most cells NF-κB exists in the cytoplasm in an inactive complex bound to IkappaB. The NF-κB network consists of five family member protein monomers (p65/RelA, RelB, cRel, p50, and p52) that form homodimers or heterodimers that bind DNA differentially and are regulated by two pathways: the canonical, NF-κB essential modulator (NEMO)-dependent pathway and the noncanonical, NEMO-independent pathway.

The I Bs bind to NF-κB dimers and sterically block the function of their NLSs, thereby causing their cytoplasmic retention. Potent NF-κB activators, such as TNFα and IL-1, cause almost complete degradation of IκBs (especially I B ) by the 26S proteasome, and NF-κB is activated and enters the nucleus. Nfkb2/p100 is the primary signaling node at which canonical and noncanonical signals interact. NIK/IKK1 processes p100 into p52, enabling the activity of RelB, NIK degrades IκBδ, allowing for sustained RelA activity, and canonical pathway activity may boost noncanonical pathway activation of RelB:p52.

Activation of the NF-κB pathway is involved in the pathogenesis of chronic inflammatory diseases, such as asthma, rheumatoid arthritis, and inflammatory bowel disease. In addition, altered NF-κB regulation may be involved in other diseases such as atherosclerosis and Alzheimer’s disease and a variety of human cancers. Therefore, numerous drugs, natural products, and normal or recombinant proteins that inhibits NF-κB activation can used in the treatment of NF-κB-related diseases.

 

参考文献:

[1] Karin M. Oncogene. 1999 Nov 22;18(49):6867-74.

[2] Yamamoto Y, et al. J Clin Invest. 2001 Jan;107(2):135-42.

[3] Mitchell S, et al. Wiley Interdiscip Rev Syst Biol Med. 2016 May;8(3):227-41.

 

PI3K/Akt/mTOR | PI3K/Akt/mTOR 信号通路

The PI3K/Akt/mTOR signaling pathways is crucial to many aspects of cell growth and survival, in physiological as well as in pathological conditions. PI3Ks constitute a lipid kinase family. Class I PI3Ks are heterodimers composed of a catalytic (CAT) subunit (i.e., p110) and an adaptor/regulatory subunit (i.e., p85), and can be further divided into two subclasses: subclass IA (PI3Kα, β, and δ), which is activated by receptors with protein tyrosine kinase activity, and subclass IB (PI3Kγ), which is activated by receptors coupled with G proteins. Akt kinases belong to the AGC kinase family, related to AMP/GMP kinases and protein kinase C. mTOR is a key protein evolutionarily conserved from yeast to man and is essential for life. The mTORC1 complex is made up of mTOR, Raptor, mLST8, and PRAS40, and the mTORC2 complex is composed of mTOR, Rictor, Sin1, and mLST8.

Upon ligand binding, phosphorylated tyrosine residing in activated RTKs will bind to p85, then release the catalytic subunit p110. Activated p110 phosphorylated the PIP2 into the second messenger PIP3, and this reaction can be reversed by the PI3K antagonist PTEN. PIP3 will recruit the downstream Akt to inner membranes and phosphorylates Akt on its serine/threonine kinase sites (Thr308 and Ser473). Activated Akt is involved in the downstream mTORC1 mediated response to biogenesis of protein and ribosome.

Many genes belonging to the PI3K/Akt pathway have been implicated in the pathophysiology of solid tumors and sensitivity/resistance to chemotherapy. More and more studies are now focusing on the translational relevance of targeting these pathways in cancer therapy.

 

参考文献:

[1] Porta C, et al. Front Oncol. 2014 Apr 14;4:64.

[2] Follo MY, et al. Adv Biol Regul. 2015 Jan;57:10-6.

[3] Li X, et al. Oncotarget. 2016 May 31;7(22):33440-50.

 

Stem Cell/Wnt | 干细胞及 Wnt 通路

Stem cells are required for continuous tissue maintenance within diverse organs, stem cell activity is often externally dictated by the microenvironment (the niche) so that stem cell output is precisely shaped to meet homeostatic needs or regenerative demands. Several key signaling pathways have been shown to play essential roles in this regulatory capacity. Specifically, the JAK/STAT, Hedgehog, Wnt, Notch, Smad, PI3K/phosphatase and tensin homolog, and NK-κB signaling pathways have all been shown experimentally to mediate various stem cell properties, such as self-renewal, cell fate decisions, survival, proliferation, and differentiation.

Recent studies mainly focus on cancer stem cell, induced pluripotent stem cell, neural stem cell and maintenance of embryonic stem cell pluripotency. Cancer stem cells (CSCs) have been believed to be responsible for tumor initiation, growth, and recurrence. Numerous agents have been developed to specifically target CSCs by suppressing the expression of pluripotency maintaining factors Nanog, Oct-4, Sox-2, and c-Myc and transcription of GLI. Induced pluripotent stem cells (iPSCs) have the capacity to differentiate into various types of cells, and a self-renewing resource, and scientists can experiment with an unlimited number of pluripotent cells to perfect the process of targeted differentiation, transplantation, and more, for personalized medicine. Novel pathological mechanisms have been elucidated, new drugs originating from iPSC screens are in the pipeline and the first clinical trial using human iPSC-derived products has been initiated.

 

参考文献:

[1] Clevers H, et al. Science. 2014 Oct 3;346(6205):1248012.

[2] Matsui WH. Medicine (Baltimore). 2016 Sep;95(1 Suppl 1):S8-S19.

[3] Koury J, et al. Stem Cells Int. 2017;2017:2925869.

[4] Garg A, et al. Cells. 2017 Feb 2;6(1). doi: 10.3390/cells6010004

 

PROTAC | 蛋白降解靶向嵌合体

PROTACs or Proteolysis Targeting Chimeric Molecules are heterobifunctional nanomolecules that theoretically target any protein for ubiquitination and degradation. In terms of the structure, PROTACs consist of one moiety which is recognized by the E3 ligase. This moiety is then chemically and covalently linked to a small molecule or a protein that recognizes the target protein. The trimeric complex formation leads to the transfer of ubiquitins to the target protein.

By removing target proteins directly rather than merely blocking them, PROTACs can provide multiple advantages over small molecule inhibitors, which can require high systemic exposure to achieve sufficient inhibition, often resulting in toxic side effects and eventual drug resistance. PROTAC molecules possess good tissue distribution and the ability to target intracellular proteins, thus can be directly applied to cells or injected into animals without the use of vectors.

Targeted protein degradation using the PROTAC technology is emerging as a novel therapeutic method to address diseases, such as cancer, driven by the aberrant expression of a disease-causing protein. In addition to the use of PROTACs for the treatment of human disease, these molecules provide a chemical genetic approach to “knock down” proteins to study their function. Currently, there are several small molecule inhibitors that have been found to show good biological activity by specifically targeting BET, estrogen receptor (ER), androgen receptor, etc.

LYTAC, AUTAC and ATTEC are PROTAC degraders specifically targeting membrane proteins via lysosomal pathway. SNIPER and molecular glue are special PROTACs, while SNIPER consists of ligand for RING E3 ligase family and molecular glue comprises a short or almost no linker.

 

参考文献:

[1] Sakamoto KM. Pediatr Res. 2010 May;67(5):505-8.

[2] Neklesa TK, et al. Pharmacol Ther. 2017 Jun;174:138-144.

[3] Ding Y. Trends Pharmacol Sci. 2020, 41(7):464-474.

[4] Schreiber S L. Cell, 2021, 184(1):3-9.

Membrane Transporter/Ion Channel | 跨膜转运
Membrane Transporter/Ion Channel——ATP Synthase Membrane Transporter/Ion Channel——BCRP Membrane Transporter/Ion Channel——Calcium Channel Membrane Transporter/Ion Channel——CFTR Membrane Transporter/Ion Channel——Chloride Channel Membrane Transporter/Ion Channel——CRAC Channel Membrane Transporter/Ion Channel——CRM1 Membrane Transporter/Ion Channel——EAAT Membrane Transporter/Ion Channel——GABA Receptor Membrane Transporter/Ion Channel——HCN Channel Membrane Transporter/Ion Channel——GLUT Membrane Transporter/Ion Channel——GlyT Membrane Transporter/Ion Channel——iGluR Membrane Transporter/Ion Channel——Monoamine Transporter Membrane Transporter/Ion Channel——Monocarboxylate Transporter Membrane Transporter/Ion Channel——Na+/Ca2+ Exchanger Membrane Transporter/Ion Channel——Na+/HCO3- Cotransporter Membrane Transporter/Ion Channel——Na+/K+ ATPase Membrane Transporter/Ion Channel——nAChR Membrane Transporter/Ion Channel——NKCC Membrane Transporter/Ion Channel——P-glycoprotein Membrane Transporter/Ion Channel——P2X Receptor Membrane Transporter/Ion Channel——Potassium Channel Membrane Transporter/Ion Channel——Proton Pump Membrane Transporter/Ion Channel——SGLT Membrane Transporter/Ion Channel——Sodium Channel Membrane Transporter/Ion Channel——TRP Channel Membrane Transporter/Ion Channel——URAT1 Membrane Transporter/Ion Channel——VDAC Membrane Transporter/Ion Channel——Aquaporin Membrane Transporter/Ion Channel——Apical Sodium-Dependent Bile Acid Transporter Membrane Transporter/Ion Channel——Calmodulin Membrane Transporter/Ion Channel——Na+/H+ Exchanger (NHE) Membrane Transporter/Ion Channel——Urea Transporter Membrane Transporter/Ion Channel——Piezo Channel

Most of molecules enter or leave cells mainly via membrane transport proteins, which play important roles in several cellular functions, including cell metabolism, ion homeostasis, signal transduction, binding with small molecules in extracellular space, the recognition process in the immune system, energy transduction, osmoregulation, and physiological and developmental processes. There are three major types of transport proteins, ATP-powered pumps, channel proteins and transporters.

ATP-powered pumps are ATPases that use the energy of ATP hydrolysis to move ions or small molecules across a membrane against a chemical concentration gradient or electric potential. Channel proteins transport water or specific types of ions down their concentration or electric potential gradients. Many other types of channel proteins are usually closed, and open only in response to specific signals. Because these types of ion channels play a fundamental role in the functioning of nerve cells. Transporters, a third class of membrane transport proteins, move a wide variety of ions and molecules across cell membranes. Membrane transporters either enhance or restrict drug distribution to the target organs. Depending on their main function, these membrane transporters are divided into two categories: the efflux (export) and the influx (uptake) transporters.

Transport proteins such as channels and transporters play important roles in the maintenance of intracellular homeostasis, and mutations in these transport protein genes have been identified in the pathogenesis of a number of hereditary diseases. In the central nervous system ion channels have been linked to many diseases such, but not limited to, ataxias, paralyses, epilepsies, and deafness indicative of the roles of ion channels in the initiation and coordination of movement, sensory perception, and encoding and processing of information. Furthermore, drug transporters can serve as drug targets or as a mechanism to facilitate drug delivery to cells and tissues.

 

参考文献:

[1] Sadée W, et al. Pharm Res. 1995 Dec;12(12):1823-37.

[2] Girardin F. Dialogues Clin Neurosci. 2006;8(3):311-21.

[3] Zaydman MA, et al. Chem Rev. 2012 Dec 12;112(12):6319-33.

[4] Mishra NK, et al. PLoS One. 2014 Jun 26;9(6):e100278.

 

Epigenetics | 表观遗传学

Epigeneics include any process that alters gene activity without changing the DNA sequence, and leads to modifications that can be transmitted to daughter cells. Many types of epigenetic processes have been identified—they include DNA methylation, alteration in the structure of histone proteins and gene regulation by small noncoding microRNAs.

Many different DNA and histone modifications have been identified to determine the epigenetic landscape. DNA methylation is mainly mediated by DNA-methyl transferase (DNMT), there are two known types of DNMT, namely DNMT1, which preserves preexisting pattern of methylation after cell replication, and DNMT3A/B, so-called “de novo” DNMT, which methylate previously unmethylated DNA. Histone modifications mainly include acetylation, methylation, phosphorylation, and ubiquitination. The acetylation of histones can be mediated by histone acetyltransferases (HATs) and histone deacetyltransferases (HDACs), while Histhone demethylation is performed by two classes of histone demethylases: lysine-specific demethylase (LSD) family proteins (LSD1 and LSD2) and JmjC domain containing histone demethylase (JHDM). Furthermore, enzymes involved in epigenetic modifications can also be governed by miRNAs. For example, miR-34a can directly inhibit the activities of SIRT1 to regulate cholesterol homeostasis.

The accumulated evidence indicates that many genes, diseases, and environmental substances are part of the epigenetics picture. At the FDA, scientists are investigating many drugs that function through epigenetic mechanisms. Drugs that inhibit DNA methylation or histone deacetylation have been studied for the reactivation of tumor suppressor genes and repression of cancer cell growth. Epigenetic inhibitors can also work alone or in combination with other therapeutic agents.

 

参考文献:

[1] Bob Weinhold. Environ Health Perspect. 2006 Mar; 114(3): A160-A167.

[2] Xu W, et al. Genet Epigenet. 2016 Sep 25;8:43-51.

[3] Biswas S, et al. Pharmacol Ther. 2017 May;173:118-134.

[4] Perri F, et al. Crit Rev Oncol Hematol. 2017 Mar;111:166-172.

 

Cytoskeleton | 细胞骨架

The cytoskeleton is a filamentous network of F-actin, microtubules, and intermediate filaments (IFs) composed of one of three chemically distinct subunits, actin, tubulin, or one of several classes of IF protein. Cytoskeleton not only helps cells maintain their shape and internal organization, but also provides mechanical support that enables cells to carry out essential functions like division and movement.

The cytoskeleton is involved in intracellular signal transduction at least two ways. First, individual proteins of the cytoskeleton might participate directly in signal transduction by linking two or more signaling proteins. Second, the cytoskeleton might provide a macromolecular scaffold, which spatially organizes components of a signal transduction cascade. Cell migration is a complex and multistep process involved in homeostasis maintenance, morphogenesis, and disease development, such as cancer metastasis, and requires coordination of cytoskeletal dynamics and reorganization, cell adhesion, and signal transduction, and takes a variety of forms. Many signaling pathways including Rho-family GTPases, Paxillin/FAK signaling and PI3K signaling is involved in the process by regulating cytoskeletal activity.

Since the cytoskeleton is involved in virtually all cellular processes, abnormalities in this essential cellular component frequently result in disease. Drugs that modulate microtubule stability, inhibitors of posttranslational modifications of cytoskeletal components, specifically compounds affecting the levels of tubulin acetylation, and compounds targeting signaling molecules which regulate cytoskeleton dynamics, constitute the mostly addressed therapeutic interventions for the diseases including cancer and neurodegenerative disorders.

 

参考文献:

[1] Janmey PA. Physiol Rev. 1998 Jul;78(3):763-81.

[2] Forgacs G, et al. J Cell Sci. 2004 Jun 1;117(Pt 13):2769-75.

[3] Eira J, et al. . Prog Neurobiol. 2016 Jun;141:61-82.

Natural Lipids | 天然脂质
Anti-infection | 抗感染

Anti-infectives are drugs that can either kill an infectious agent or inhibit it from spreading. Anti-infectives include antibiotics and antibacterials, antifungals, antivirals and antiprotozoals.

Antibiotics specifically treat infections caused by bacteria, most commonly used types of antibiotics are: Aminoglycosides, Penicillins, Fluoroquinolones, Cephalosporins, Macrolides, and Tetracyclines. New other approaches such as photodynamic therapy (PDT) and antibacterial peptides have been considered as alternatives to kill bacteria.

The high rates of morbidity and mortality caused by fungal infections are associated with the current limited antifungal arsenal and the high toxicity of the compounds. The most common antifungal targets include fungal RNA synthesis and cell wall and membrane components, though new antifungal targets are being investigated.

Viral infections occur when viruses enter cells in the body and begin reproducing, often causing illness. Viruses are classified as DNA viruses or RNA viruses, RNA viruses include retroviruses, such as HIV, are prone to mutate. The currently available antiviral drugs target 4 main groups of viruses: herpes, hepatitis, HIV and influenza viruses. Drug resistance in the clinical utility of antiviral drugs has raised an urgent need for developing new antiviral drugs.

Antiprotozoal drugs are medicines that treat infections caused by protozoa. Of which, malaria remains a major world health problem following the emergence and spread of Plasmodium falciparum that is resistant to the majority of antimalarial drugs. At present, antimalarial discovery approaches have been studied, such as the discovery of antimalarials from natural sources, chemical modifications of existing antimalarials, the development of hybrid compounds, testing of commercially available drugs that have been approved for human use for other diseases and molecular modelling using virtual screening technology and docking.

 

参考文献:

[1] Scorzoni L, et al. Front Microbiol. 2017 Jan 23;8:36.

[2] Dehghan Esmatabadi MJ, et al. Cell Mol Biol (Noisy-le-grand). 2017 Feb 28;63(2):40-48.

[3] Raymund R, et al. Mayo Clin Proc. 2011 Oct; 86(10):1009-1026.

[4] Aguiar AC, et al. Mem Inst Oswaldo Cruz. 2012 Nov;107(7):831-45.

Metabolic Enzyme/Protease | 代谢酶/蛋白酶
Metabolic Enzyme/Protease——Aldose Reductase Metabolic Enzyme/Protease——Carbonic Anhydrase Metabolic Enzyme/Protease——Enolase Metabolic Enzyme/Protease——Glucokinase Metabolic Enzyme/Protease——Glucosidase Metabolic Enzyme/Protease——Glutathione Peroxidase Metabolic Enzyme/Protease——Hexokinase Metabolic Enzyme/Protease——HIF/HIF Prolyl-Hydroxylase Metabolic Enzyme/Protease——NADPH Oxidase Metabolic Enzyme/Protease——Lactate Dehydrogenase Metabolic Enzyme/Protease——Mineralocorticoid Receptor Metabolic Enzyme/Protease——Mitochondrial Metabolism Metabolic Enzyme/Protease——NAMPT Metabolic Enzyme/Protease——PGC-1α Metabolic Enzyme/Protease——Phosphatase Metabolic Enzyme/Protease——Pyruvate Kinase Metabolic Enzyme/Protease——Reactive Oxygen Species Metabolic Enzyme/Protease——SGK Metabolic Enzyme/Protease——15-PGDH Metabolic Enzyme/Protease——5 alpha Reductase Metabolic Enzyme/Protease——Acetyl-CoA Carboxylase Metabolic Enzyme/Protease——Acyltransferase Metabolic Enzyme/Protease——Aldehyde Dehydrogenase (ALDH) Metabolic Enzyme/Protease——ATGL Metabolic Enzyme/Protease——ATP Citrate Lyase Metabolic Enzyme/Protease——CETP Metabolic Enzyme/Protease——Cytochrome P450 Metabolic Enzyme/Protease——Epoxide Hydrolase Metabolic Enzyme/Protease——FAAH Metabolic Enzyme/Protease——FABP Metabolic Enzyme/Protease——Fatty Acid Synthase (FASN) Metabolic Enzyme/Protease——FXR Metabolic Enzyme/Protease——HMG-CoA Reductase (HMGCR) Metabolic Enzyme/Protease——Isocitrate Dehydrogenase (IDH) Metabolic Enzyme/Protease——Lipoxygenase Metabolic Enzyme/Protease——LXR Metabolic Enzyme/Protease——MAGL Metabolic Enzyme/Protease——Mitochondrial Metabolism Metabolic Enzyme/Protease——PDHK Metabolic Enzyme/Protease——PGC-1α Metabolic Enzyme/Protease——Phosphatase Metabolic Enzyme/Protease——Phospholipase Metabolic Enzyme/Protease——RAR/RXR Metabolic Enzyme/Protease——Reactive Oxygen Species Metabolic Enzyme/Protease——ROR Metabolic Enzyme/Protease——Stearoyl-CoA Desaturase (SCD) Metabolic Enzyme/Protease——Adenosine Deaminase Metabolic Enzyme/Protease——Adenosine Kinase Metabolic Enzyme/Protease——Aminopeptidase Metabolic Enzyme/Protease——Angiotensin-converting Enzyme (ACE) Metabolic Enzyme/Protease——Arginase Metabolic Enzyme/Protease——Carboxypeptidase Metabolic Enzyme/Protease——Cathepsin Metabolic Enzyme/Protease——COMT Metabolic Enzyme/Protease——Dipeptidyl Peptidase Metabolic Enzyme/Protease——Dopamine β-hydroxylase Metabolic Enzyme/Protease——E1/E2/E3 Enzyme Metabolic Enzyme/Protease——Elastase Metabolic Enzyme/Protease——Factor Xa Metabolic Enzyme/Protease——Farnesyl Transferase Metabolic Enzyme/Protease——Glutaminase Metabolic Enzyme/Protease——GSNOR Metabolic Enzyme/Protease——Gutathione S-transferase Metabolic Enzyme/Protease——HCV Protease Metabolic Enzyme/Protease——HIV Protease Metabolic Enzyme/Protease——HSP Metabolic Enzyme/Protease——Indoleamine 2,3-Dioxygenase (IDO) Metabolic Enzyme/Protease——Isocitrate Dehydrogenase (IDH) Metabolic Enzyme/Protease——MALT1 Metabolic Enzyme/Protease——MMP Metabolic Enzyme/Protease——NADPH Oxidase Metabolic Enzyme/Protease——NEDD8-activating Enzyme Metabolic Enzyme/Protease——Neprilysin Metabolic Enzyme/Protease——PAI-1 Metabolic Enzyme/Protease——Phosphatase Metabolic Enzyme/Protease——Procollagen C Proteinase Metabolic Enzyme/Protease——Proteasome Metabolic Enzyme/Protease——Reactive Oxygen Species Metabolic Enzyme/Protease——Renin Metabolic Enzyme/Protease——Ser/Thr Protease Metabolic Enzyme/Protease——Thrombin Metabolic Enzyme/Protease——Tryptophan Hydroxylase Metabolic Enzyme/Protease——Tyrosinase Metabolic Enzyme/Protease——Xanthine Oxidase Metabolic Enzyme/Protease——Aminoacyl-tRNA Synthetase Metabolic Enzyme/Protease——Dihydroorotate Dehydrogenase Metabolic Enzyme/Protease——HIV Integrase Metabolic Enzyme/Protease——Phosphodiesterase (PDE) Metabolic Enzyme/Protease——Drug Metabolite Metabolic Enzyme/Protease——Endogenous Metabolite Metabolic Enzyme/Protease——Liposome Metabolic Enzyme/Protease——Amylases Metabolic Enzyme/Protease——Ceramidase Metabolic Enzyme/Protease——Cryptochrome Metabolic Enzyme/Protease——DGK Metabolic Enzyme/Protease——Dihydrofolate reductase (DHFR) Metabolic Enzyme/Protease——Furin Metabolic Enzyme/Protease——FBPase Metabolic Enzyme/Protease——Factor VIII Metabolic Enzyme/Protease——Fat Mass and Obesity-associated Protein (FTO) Metabolic Enzyme/Protease——Methionine Adenosyltransferase (MAT) Metabolic Enzyme/Protease——Methylenetetrahydrofolate Dehydrogenase (MTHFD) Metabolic Enzyme/Protease——Microsomal Triglyceride Transfer Protein (MTP) Metabolic Enzyme/Protease——PEPCK Metabolic Enzyme/Protease——Prolyl Endopeptidase (PREP) Metabolic Enzyme/Protease——Phosphoglycerate Dehydrogenase (PHGDH) Metabolic Enzyme/Protease——Glyoxalase (GLO) Metabolic Enzyme/Protease——TrxR Metabolic Enzyme/Protease——Transketolase Metabolic Enzyme/Protease——17β-HSD Metabolic Enzyme/Protease——11β-HSD Metabolic Enzyme/Protease——LDLR Metabolic Enzyme/Protease——HPPD Metabolic Enzyme/Protease——Acetolactate Synthase (ALS) Metabolic Enzyme/Protease——Dehydrogenase Metabolic Enzyme/Protease——UGT Metabolic Enzyme/Protease——REV-ERB

Metabolic pathways are enzyme-mediated biochemical reactions that lead to biosynthesis (anabolism) or breakdown (catabolism) of natural product small molecules within a cell or tissue. In each pathway, enzymes catalyze the conversion of substrates into structurally similar products. Metabolic processes typically transform small molecules, but also include macromolecular processes such as DNA repair and replication, and protein synthesis and degradation. Metabolism maintains the living state of the cells and the organism.

Proteases are used throughout an organism for various metabolic processes. Proteases control a great variety of physiological processes that are critical for life, including the immune response, cell cycle, cell death, wound healing, food digestion, and protein and organelle recycling. On the basis of the type of the key amino acid in the active site of the protease and the mechanism of peptide bond cleavage, proteases can be classified into six groups: cysteine, serine, threonine, glutamic acid, aspartate proteases, as well as matrix metalloproteases. Proteases can not only activate proteins such as cytokines, or inactivate them such as numerous repair proteins during apoptosis, but also expose cryptic sites, such as occurs with β-secretase during amyloid precursor protein processing, shed various transmembrane proteins such as occurs with metalloproteases and cysteine proteases, or convert receptor agonists into antagonists and vice versa such as chemokine conversions carried out by metalloproteases, dipeptidyl peptidase IV and some cathepsins. In addition to the catalytic domains, a great number of proteases contain numerous additional domains or modules that substantially increase the complexity of their functions.

Imbalances in metabolic activities have been found to be critical in a number of pathologies, such as cardiovascular diseases, inflammation, cancer, and neurodegenerative diseases.

 

参考文献:

[1] Turk B, et al. EMBO J. 2012 Apr 4;31(7):1630-43.

[2] Eatemadi A, et al. Biomed Pharmacother. 2017 Feb;86:221-231.

 

Vitamin D Related | 维生素 D 相关

Vitamin D was first identified as a cure for nutritional rickets, a disease of bone growth caused by an inadequate uptake of dietary calcium. Vitamin D refers collectively to vitamin D3 and vitamin D2. Biologically active vitamin D is generated via largely hepatic 25-hydroxylation catalyzed by CYP2R1, CYP27A1, and possibly other enzymes to produce 25-hydroxvitamin D (25D), which has a long half-life and is the major circulating vitamin D metabolite. 25D is modified by 1α-hydroxylation catalyzed by CYP27B1, which produces hormonal 1,25-dihydroxyvitamin D (1,25D).

The biological actions of 1,25(OH)2D3 are mediated by the VDR. VDR belongs to the steroid receptor family which includes receptors for retinoic acid, thyroid hormone, sex hormones, and adrenal steroids. The genomic mechanism of 1,25(OH)2D3 action involves the direct binding of the 1,25(OH)2D3 activated vitamin D receptor/retinoic X receptor (VDR/RXR) heterodimeric complex to specific DNA sequences. 1,25(OH)2D3 action regulates renal calcium reabsorption and phosphate loss, and thus control bone metabolism mainly indirectly by regulating mineral homeostasis.

Vitamin D deficiency increases rates of cancer, as well as autoimmune and infectious diseases. More than 3,000 vitamin D analogs are developed worldwide and several analogs demonstrated more potent antiproliferative and prodifferentating effects on cancer cell lines compared with 1,25(OH)2D3, which may lead to the development of new therapies to prevent and treat diseases.

 

参考文献:

[1] White JH. Infect Immun. 2008 Sep;76(9):3837-43.

[2] Christakos S, et al. Physiol Rev. 2016 Jan;96(1):365-408.

Pyroptosis | 细胞焦亡

Pyroptosis is a type of programmed cell death that features pore formation on the plasma membrane, cell swelling and plasma membrane disruption. Pyroptosis is a form of lytic programmed cell death initiated by inflammasomes, which detect cytosolic contamination or perturbation.

Gasdermin D (GSDMD), as the executive protein of pyroptosis, is activated and transferred to the membrane to induce glial rupture, resulting in the release of more inflammatory mediators.

Inflammasome is an intracellular signaling complex of the innate immune system. Activation of inflammasomes promotes the secretion of IL-1β/IL-18 and triggers pyroptosis. The proinflammatory effect of IL-1β/IL-18 and pyroptosis contributes to the development of autoimmune and inflammatory diseases.

Inhibitory Antibodies | 抗体抑制剂
Others | 其他
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