グリコーゲン代謝酵素の調節

Glycogen phosphorylase, liver form

Phosphorylase is an important allosteric enzyme in carbohydrate metabolism. Enzymes from different sources differ in their regulatory mechanisms and in their natural substrates. However, all known phosphorylases share catalytic and structural properties.
Activity of phosphorylase is controlled both by allosteric means (through the noncovalent binding of metabolites) and by covalent modification. Thus AMP allosterically activates, whereas ATP, ADP, and glucose-6-phosphate allosterically inhibit, phosphorylase B.
AMPがアロステリック活性化因子、ATP、ADP、G6-Pがアロステリック阻害因子

Glycogen phosphorylase, muscle form

Activity of phosphorylase is controlled both by allosteric means (through the noncovalent binding of metabolites) and by covalent modification. Thus AMP allosterically activates, whereas ATP, ADP, and glucose-6-phosphate allosterically inhibit, phosphorylase B.

Glycogen [starch] synthase, liver

Transfers the glycosyl residue from UDP-Glc to the non-reducing end of alpha-1,4-glucan.
Allosteric activation by glucose-6-phosphate. Phosphorylation reduces the activity towards UDP-glucose. When in the non-phosphorylated state, glycogen synthase does not require glucose-6-phosphate as an allosteric activator; when phosphorylated it does (By similarity).
G6-Pがアロステリック活性化因子
リン酸化によりUDP-グルコースに対する活性が低下する。非リン酸化状態で、グリコーゲンシンターゼの活性にG6-Pによる活性化は不要である。

Glycogen [starch] synthase, muscle

Allosteric activation by glucose-6-phosphate. Phosphorylation reduces the activity towards UDP-glucose. When in the non-phosphorylated state, glycogen synthase does not require glucose-6-phosphate as an allosteric activator; when phosphorylated it does (By similarity).

グルコーストランスポーター

GLUT1

• Facilitative glucose transporter. This isoform may be responsible for constitutive or basal glucose uptake. Has a very broad substrate specificity; can transport a wide range of aldoses including both pentoses and hexoses.
• Detected in erythrocytes (at protein level). Expressed at variable levels in many human tissues.

GLUT-2

• Facilitative glucose transporter. This isoform likely mediates the bidirectional transfer of glucose across the plasma membrane of hepatocytes and is responsible for uptake of glucose by the beta cells; may comprise part of the glucose-sensing mechanism of the beta cell. May also participate with the Na+/glucose cotransporter in the transcellular transport of glucose in the small intestine and kidney.
• Liver, insulin-producing beta cell, small intestine and kidney.

GLUT-3

• Facilitative glucose transporter that can also mediate the uptake of various other monosaccharides across the cell membrane. Mediates the uptake of glucose, 2-deoxyglucose, galactose, mannose, xylose and fucose, and probably also dehydroascorbate . Does not mediate fructose transport.
• Highly expressed in brain. Expressed in many tissues.

GLUT-4

• Insulin-regulated facilitative glucose transporter.
• Insulin-stimulated phosphorylation of TBC1D4 is required for GLUT4 translocation.
• expressed in Skeletal and cardiac muscles; brown and white fat.
• Diabetes mellitus, non-insulin-dependent (NIDDM)3 Publications:0The disease may be caused by mutations affecting the gene represented in this entry.

Disease descriptionA multifactorial disorder of glucose homeostasis caused by a lack of sensitivity to the body's own insulin. Affected individuals usually have an obese body habitus and manifestations of a metabolic syndrome characterized by diabetes, insulin resistance, hypertension and hypertriglyceridemia. The disease results in long-term complications that affect the eyes, kidneys, nerves, and blood vessels.

GLUT-5

• Functions as a fructose transporter that has only low activity with other monosaccharides (PubMed:8333543). Can mediate the uptake of 2-deoxyglucose, but with low efficiency (PubMed:1695905). Essential for fructose uptake in the small intestine. Plays a role in the regulation of salt uptake and blood pressure in response to dietary fructose. Required for the development of high blood pressure in response to high dietary fructose intake.
• The uptake of 2-deoxyglucose is inhibited by cytochalasin B.
• Detected in skeletal muscle, and in jejunum brush border membrane and basolateral membrane (at protein level) (PubMed:7619085). Expressed in small intestine, and at much lower levels in kidney, skeletal muscle, and adipose tissue.

GLUT7

• High-affinity transporter for glucose and fructose Does not transport galactose, 2-deoxy-d-glucose and xylose.
• Expressed in small intestine and colon. Weakly expressed in testis and prostate.

GLUT8

• Insulin-regulated facilitative glucose transporter. Binds cytochalasin B in a glucose-inhibitable manner. Seems to be a dual-specific sugar transporter as it is inhibitable by fructose (By similarity).

GLUT9

• Transport urate and fructose. May have a role in the urate reabsorption by proximal tubules. Also transports glucose at low rate.
• Solute carrier family 2, facilitated glucose transporter member 9 (SLC2A9)
• Most strongly expressed in basolateral membranes of proximal renal tubular cells, liver and placenta. Also detected in lung, blood leukocytes, heart skeletal muscle and chondrocytes from articular cartilage.

GLUT10

• Facilitative glucose transporter.

GLUT14

• May have a specific function related to spermatogenesis.
• GLUT14 is a recent (less than 5 M year old) duplication of GLUT3.

血漿カリクレイン（血漿プレカリクレイン）

カリクレイン重鎖と軽鎖に切断される
The enzyme cleaves Lys-Arg and Arg-Ser bonds. It activates, in a reciprocal reaction, factor XII after its binding to a negatively charged surface. It also releases bradykinin from HMW kininogen and may also play a role in the renin-angiotensin system by converting prorenin into renin.
Lys-ArgまたはArg-Serを切断する活性をもつ
第12因子と陰性荷電表面に結合した後相互に活性化する。HMW-キニノーゲンからブラジキニンを遊離させ、レニン−アンギオテンシン系にプロレニンをレニンに変換することで関与する

カリクレイン

生化学辞典第４版301ページ
血漿カリクレインと腺性カリクレインがある。
セリンプロテアーゼ。
哺乳動物の血漿中にプレカリクレイン（分子量12万程度の糖タンパク質）として存在し、活性化第Ⅻ因子により分解されて活性化し、高分子キニノーゲンを切断してブラジキニンを遊離させる。

高分子量キニノーゲン（キニノーゲン-1）

1 Kininogens are inhibitors of thiol proteases; (2) HMW-kininogen plays an important role in blood coagulation by helping to position optimally prekallikrein and factor XI next to factor XII; (3) HMW-kininogen inhibits the thrombin- and plasmin-induced aggregation of thrombocytes; (4) the active peptide bradykinin that is released from HMW-kininogen shows a variety of physiological effects: (4A) influence in smooth muscle contraction, (4B) induction of hypotension, (4C) natriuresis and diuresis, (4D) decrease in blood glucose level, (4E) it is a mediator of inflammation and causes (4E1) increase in vascular permeability, (4E2) stimulation of nociceptors (4E3) release of other mediators of inflammation (e.g. prostaglandins), (4F) it has a cardioprotective effect (directly via bradykinin action, indirectly via endothelium-derived relaxing factor action); (5) LMW-kininogen inhibits the aggregation of thrombocytes; (6) LMW-kininogen is in contrast to HMW-kininogen not involved in blood clotting.

1. チオールプロテアーゼの阻害作用をもつ
2. ＨＭＷ−キニノーゲンは血液の凝固においてプレカリクレインと第11因子を第12因子に引き続き活性化させる。
3. トロンビンとプラスミンにより誘導される血小板の凝集を阻害する
4. HMW-キニノーゲンから遊離するブラジキニンは多くの生理学的作用を示す（平滑筋収縮に影響、低血圧、ナトリウム利尿、血糖低下
5. LMW-キニノーゲンは血小板の凝集を阻害する
6. LMW-キニノーゲンは血液凝固に関与しない

第Ⅻ因子

www.uniprot.org

血液凝固の開始、線溶、ブラジキニンとアンギオテンシンの生成に関与する。
プレカリクレインは第Ⅻ因子により切断されカリクレインとなる。カリクレインはトリプシンとともに第Ⅻ因子を活性化する。第Ⅻ因子は第Ⅺ因子を活性化する。
Factor XII is a serum glycoprotein that participates in the initiation of blood coagulation, fibrinolysis, and the generation of bradykinin and angiotensin. Prekallikrein is cleaved by factor XII to form kallikrein, which then cleaves factor XII first to alpha-factor XIIa and then trypsin cleaves it to beta-factor XIIa. Alpha-factor XIIa activates factor XI to factor XIa.

Catalytic activity

Selective cleavage of Arg-|-Ile bonds in factor VII to form factor VIIa and factor XI to form factor XIa.

Post-translational modification

Factor XII is activated by kallikrein in alpha-factor XIIa, which is further converted by trypsin into beta-factor XIIa. Alpha-factor XIIa is composed of an NH2-terminal heavy chain, called coagulation factor XIIa heavy chain, and a COOH-terminal light chain, called coagulation factor XIIa light chain, connected by a disulfide bond. Beta-factor XIIa is composed of 2 chains linked by a disulfide bond, an N-terminal nonapeptide, called beta-factor XIIa part 1, and coagulation factor XIIa light chain, also known in this context as beta-factor XIIa part 2.
O- and N-glycosylated. The O-linked polysaccharides were not identified, but are probably the mucin type linked to GalNAc.
カリクレインにより活性化第Ⅻ因子α（Ｎ末端側の重鎖）とc末端側の第Ⅻ因子軽鎖に分かれる。さらにトリプシンにより活性化第Ⅻ因子βとなる。

Plasminogen

プラスミノーゲンは血栓のフィブリンを溶解するほか、多くの過程でタンパク質分解因子として働く。（胎児の発達、組織のリモデリング、腫瘍の浸潤、炎症など）
排卵ではグラーフ卵胞の破裂を促す。ウロキナーゼ型のプラスミノーゲンアクチベーター、コラゲナーゼや他の多くの補体のチモーゲン（C1とC5）により活性化される。
フィブロネクチンやラミニンの切断は細胞の遊離とアポトーシスをもたらす。フィブリンやトロンボスポンジン、VWFを分解する。
Plasmin dissolves the fibrin of blood clots and acts as a proteolytic factor in a variety of other processes including embryonic development, tissue remodeling, tumor invasion, and inflammation. In ovulation, weakens the walls of the Graafian follicle. It activates the urokinase-type plasminogen activator, collagenases and several complement zymogens, such as C1 and C5. Cleavage of fibronectin and laminin leads to cell detachment and apoptosis. Also cleaves fibrin, thrombospondin and von Willebrand factor. Its role in tissue remodeling and tumor invasion may be modulated by CSPG4. Binds to cells.
Angiostatin is an angiogenesis inhibitor that blocks neovascularization and growth of experimental primary and metastatic tumors in vivo.

Miscellaneous

Plasmin is inactivated by alpha-2-antiplasmin immediately after dissociation from the clot.

Catalytic activity

Preferential cleavage: Lys-|-Xaa > Arg-|-Xaa; higher selectivity than trypsin. Converts fibrin into soluble products.1 Publication

Enzyme regulation

Converted into plasmin by plasminogen activators, both plasminogen and its activator being bound to fibrin. Activated with catalytic amounts of streptokinase. Plasmin activity inhibited by SERPINE2.

Post-translational modificationi

N-linked glycan contains N-acetyllactosamine and sialic acid. O-linked glycans consist of Gal-GalNAc disaccharide modified with up to 2 sialic acid residues (microheterogeneity).
In the presence of the inhibitor, the activation involves only cleavage after Arg-580, yielding two chains held together by two disulfide bonds. In the absence of the inhibitor, the activation involves additionally the removal of the activation peptide.

Interleukin-1 receptor-associated kinase 1

• http://www.uniprot.org/uniprot/P51617

Function

Serine/threonine-protein kinase that plays a critical role in initiating innate immune response against foreign pathogens. Involved in Toll-like receptor (TLR) and IL-1R signaling pathways. Is rapidly recruited by MYD88 to the receptor-signaling complex upon TLR activation. Association with MYD88 leads to IRAK1 phosphorylation by IRAK4 and subsequent autophosphorylation and kinase activation. Phosphorylates E3 ubiquitin ligases Pellino proteins (PELI1, PELI2 and PELI3) to promote pellino-mediated polyubiquitination of IRAK1. Then, the ubiquitin-binding domain of IKBKG/NEMO binds to polyubiquitinated IRAK1 bringing together the IRAK1-MAP3K7/TAK1-TRAF6 complex and the NEMO-IKKA-IKKB complex. In turn, MAP3K7/TAK1 activates IKKs (CHUK/IKKA and IKBKB/IKKB) leading to NF-kappa-B nuclear translocation and activation. Alternatively, phosphorylates TIRAP to promote its ubiquitination and subsequent degradation. Phosphorylates the interferon regulatory factor 7 (IRF7) to induce its activation and translocation to the nucleus, resulting in transcriptional activation of type I IFN genes, which drive the cell in an antiviral state. When sumoylated, translocates to the nucleus and phosphorylates STAT3.
セリントレオニンキナーゼで自然免疫の開始に重要な役割。Toll-like receptorとIL-1受容体のシグナル伝達路に含まれる。
MYD88により受容体シグナル伝達複合体に取り込まれてTLR活性化に関与する。IRAK4によるリン酸化と引き続き自己リン酸化でキナーゼ活性が活性化される。