히스티딘 Histidine, imidazole sidechain

단백질 ≫ 아미노산 ≫ 아미노산 합성

히스티딘 Histidine

- Gluamic acid, glutamine
- Aspartic acid, asparagine
- serine, threonine, glycine, valine
- alanine, leucine, isoleucine
- lysine, arginine, histidine, proline
- methionine, Cysteine
- Tyrosine, Phenylalanie, Tryptophan

여러 가지 단백질 속에 함유되어 있는데, 가장 많이 포함한 것으로는 혈액 속의   헤모글로빈으로 약 11% 함유
아민기가 있는 아르기닌, 라이신과 함께 이미다졸(imidazole) 작용기 덕분에 염기성을 띤다.
근육을 구성하는 성분 중 하나인 카르노신에 쓰이기 때문에 단백질 보충제에 포함되어 있는 경우가 많다. 또한 위액 분비 촉진, 혈구 생성, 관절염 및 알레르기 증상 개선, 신경세포 보호, 중금속 및 방사선에 대한 저항력 증가 등의 기능이 알려져 있다.

또한 많은 효소의 활성 부위에는 히스티딘이 존재해 효소 반응에 중심적인 역할을 한다. 이는 히스티딘의 곁가지에 달려 있는 이미다졸(imidazole) 고리 때문이다. 이미다졸 고리의 두 개의 질소 원자는 모두 양이온를 받았다가 내놓았다가를 할 수 있으며, 또한 이 이미다졸의 작용기 pKa가 7에 근접하기 때문에 중성인 체내에서 약간의 변화만 가해도 H+의 해리를 쉽게 조절할 수 있다. 이를 통해 효소는 기질에 H+를 주거나 가져가는 과정을 효과적으로 촉매할 수 있게 된다.
또한 이 이미다졸의 성질을 이용해 단백질 크로마토그래피에 히스티딘을 사용하기도 한다. 앞서 말했다시피 이미다졸의 질소는 양이온을 쉽게 내놓아 음극성을 띠게 된다. 이러한 음극성으로 인해, 히스티딘은 금속 이온과 쉽게 결합을 형성하게 된다. 따라서 목표하는 단백질의 서열 끝자락에 다수의 히스티딘이 붙어 있고, 그 사이에 특정한 아미노산 서열이 있도록 유전자를 조작한 후, 단백질 용액을 금속 이온이 도포된 크로마토그래피에 통과시키면 목표 단백질만 금속에 달라붙어 남아있게 된다. 이를 이미다졸 용액으로 씻어낸 후, 앞서 말한 특정한 아미노산 서열에 반응해 펩타이드 결합을 끊는 효소를 처리하면 목표 단백질이 깔끔하게 분리된다.

The imidazole sidechain of histidine is a common coordinating ligand in metalloproteins and is a part of catalytic sites in certain enzymes. In catalytic triads, the basic nitrogen of histidine is used to abstract a proton from serine, threonine, or cysteine to activate it as a nucleophile. In a histidine proton shuttle, histidine is used to quickly shuttle protons, it can do this by abstracting a proton with its basic nitrogen to make a positively-charged intermediate and then use another molecule, a buffer, to extract the proton from its acidic nitrogen. In carbonic anhydrases, a histidine proton shuttle is utilized to rapidly shuttle protons away from a zinc-bound water molecule to quickly regenerate the active form of the enzyme.
 

Imidazole is incorporated into many important biological molecules. The most pervasive is the amino acid histidine, which has an imidazole side-chain. Histidine is present in many proteins and enzymes and plays a vital part in the structure and binding functions of hemoglobin. Imidazole-based histidine compounds play a very important role in intracellular buffering.[15] Histidine can be decarboxylated to histamine, which is also a common biological compound. Histamine can cause urticaria (hives) when it is produced during allergic reaction. The relationship between histidine and histamine is shown below:

One of the applications of imidazole is in the purification of His-tagged proteins in immobilised metal affinity chromatography (IMAC). Imidazole is used to elute tagged proteins bound to nickel ions attached to the surface of beads in the chromatography column. An excess of imidazole is passed through the column, which displaces the His-tag from nickel coordination, freeing the His-tagged proteins.

Imidazole has become an important part of many pharmaceuticals. Synthetic imidazoles are present in many fungicides and antifungal, antiprotozoal, and antihypertensive medications. Imidazole is part of the theophylline molecule, found in tea leaves and coffee beans, that stimulates the central nervous system. It is present in the anticancer medication mercaptopurine, which combats leukemia by interfering with DNA activities.

A number of substituted imidazoles, including clotrimazole, are selective inhibitors of nitric oxide synthase, which makes them interesting drug targets in inflammation, neurodegenerative diseases and tumors of the nervous system.[16][17] Other biological activities of the imidazole pharmacophore relate to the downregulation of intracellular Ca2+ and K+ fluxes, and interference with translation initiation.[18]

Pharmaceutical derivatives
The substituted imidazole derivatives are valuable in treatment of many systemic fungal infections.[19] Imidazoles belong to the class of azole antifungals, which includes ketoconazole, miconazole, and clotrimazole.
For comparison, another group of azoles is the triazoles, which includes fluconazole, itraconazole, and voriconazole. The difference between the imidazoles and the triazoles involves the mechanism of inhibition of the cytochrome P450 enzyme. The N3 of the imidazole compound binds to the heme iron atom of ferric cytochrome P450, whereas the N4 of the triazoles bind to the heme group. The triazoles have been shown to have a higher specificity for the cytochrome P450 than imidazoles, thereby making them more potent than the imidazoles.[20]
Some imidazole derivatives show effects on insects, for example sulconazole nitrate exhibits a strong anti-feeding effect on the keratin-digesting Australian carpet beetle larvae Anthrenocerus australis, as does econazole nitrate with the common clothes moth Tineola bisselliella.[21]