Myeloperoxidase (MPO) is a peroxidase enzyme that in humans is encoded by the MPO gene on chromosome 17. MPO is most abundantly expressed in neutrophil granulocytes (a subtype of white blood cells), and produces hypohalous acids to carry out their antimicrobial activity, including hypochlorous acid, the sodium salt of which is the chemical in bleach. It is a lysosomal protein stored in azurophilic granules of the neutrophil and released into the extracellular space during degranulation. Neutrophil myeloperoxidase has a heme pigment, which causes its green color in secretions rich in neutrophils, such as mucus and sputum. The green color contributed to its outdated name verdoperoxidase.

EC number 
The EC number of myeloperoxidase (MPO) is 1.11.2.2. The first digit, 1, places the enzyme into a class the class which catalyzes oxidoreductase reactions. The second digit, 11, classifies the enzyme as a peroxidase. The final digits, 2 and 2 identify specifically myeloperoxidase.

Reaction pathway 
The major reaction myeloperoxidase catalyzes is the conversion of hydrogen peroxide and chloride ions into hypochlorous acid. To achieve this, myeloperoxidase uses hydrogen peroxide as an electron acceptor (for breakdown) and chloride ions as substrates. This all occurs within a neutrophil cell, which is important for innate immune function. The first part of the reaction pathway is when the heme group of the myeloperoxidase is converted to an activated heme called Compound I when hydrogen peroxide donates an oxygen to myeloperoxidase. This compound then oxidizes the chloride ions to form the hypochlorous acid and Compound II, which can be reduced back down to its original heme state. This cycle continues for as long as the immune system requires. The myeloperoxidase activity within the phagosome of the neutrophil is conducive to the breakdown of pathogens, as hypochlorous acid is an effective antimicrobial agent.

Structure 

The 150-kDa MPO protein is a cationic heterotetramer consisting of two 15-kDa light chains and two variable-weight glycosylated heavy chains bound to a prosthetic heme group complex with calcium ions, arranged as a homodimer of heterodimers. The light chains are glycosylated and contain the modified iron protoporphyrin IX active site. Together, the light and heavy chains form two identical 73-kDa monomers connected by a cystine bridge at Cys153. The protein forms a deep crevice which holds the heme group at the bottom, as well as a hydrophobic pocket at the entrance to the distal heme cavity which carries out its catalytic activity.

Three isoforms have been identified, differing only in the size of the heavy chains.

One of the ligands is the carbonyl group of Asp 96. Calcium-binding is important for structure of the active site because of Asp 96's close proximity to the catalytic His95 side chain.

Function 
Myeloperoxidase's main functions are within the immune system, functioning to essentially destroy pathogens. The way this works is that they are released from granules within the neutrophil into the phagosome for breakdown of pathogens. It does this by, as described before, catalysis of hydrogen peroxide into hypochlorous acid. This hypochlorous acid, along with destruction of pathogens, can also initiate and regulate inflammatory response. Inflammatory response affects metabolic pathways when activating immune cells. In order to provide energy necessary for inflammatory response, glycolysis is upregulated to provide ATP for phagocytosis. Following phagocytosis, the immune cells repair and remodel tissues, which can be aided by oxidized products of myeloperoxidase function.

MPO is a member of the XPO subfamily of peroxidases and produces hypochlorous acid (HOCl) from hydrogen peroxide (H2O2) and chloride anion (Cl−) (or hypobromous acid if Br- is present) during the neutrophil's respiratory burst. It requires heme as a cofactor. Furthermore, it oxidizes tyrosine to tyrosyl radical using hydrogen peroxide as an oxidizing agent. Hypochlorous acid and tyrosyl radical are cytotoxic, so they are used by the neutrophil to kill bacteria and other pathogens. However, this hypochlorous acid may also cause oxidative damage in host tissue. Moreover, MPO oxidation of apoA-I reduces HDL-mediated inhibition of apoptosis and inflammation. In addition, MPO mediates protein nitrosylation and the formation of 3-chlorotyrosine and dityrosine crosslinks.

Structure effect on function 
As described before, the structure of myeloperoxidase is integral to its function. The central heme group acts as the active site for chloride ions and hydrogen peroxide. This is also the site of electron transfer, which allows myeloperoxidase to convert the two into hypochlorous acid. This allows the main function of myeloperoxidase, breakdown of pathogens, to occur.

Crystal structure 
There are many variations of the myeloperoxidase 3D structure, however they all follow a specific pattern. The myeloperoxidase enzyme typically weighs within the 135-200 kDa range, depending on the varying heavy chains it can be bound to. The enzyme is a heterotetramer with two light chains (15 kDa) and two glycosylated heavy chains which cause variability in weight. These heavy chains are bound to a heme group complex with calcium ions, arranged as a homodimer of heterodimers. The light and heavy chain monomers are connected by a cystine bridge at Cys153.

Active Sites 
The heme group containing a central iron atom functions as the active site for myeloperoxidase. This heme group is active in the oxidoreductase activity on hydrogen peroxide. This is also where substrate (Cl- ions) and hydrogen peroxide may bind. This results in a reaction with the heme iron, and the chloride ions help form hypochlorous acid. Amino acid residues participate in the transfer of electrons during the reaction catalyzed by myeloperoxidase.

Organisms containing Myeloperoxidase 
Myeloperoxidase is currently found in many different organisms including mammals, birds, fish, reptiles, and amphibians. Myeloperoxidase deficiency is a well-documented disease among humans resulting in impaired immune function.

Clinical significance 

Myeloperoxidase deficiency is a hereditary deficiency of the enzyme, which predisposes to immune deficiency.

Antibodies against MPO have been implicated in various types of vasculitis, most prominently three clinically and pathologically recognized forms: granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA); and eosinophilic granulomatosis with polyangiitis (EGPA). Antibodies are also known as anti-neutrophil cytoplasmic antibodies (ANCAs), though ANCAs have also been detected in staining of the perinuclear region.

Recent studies have reported an association between elevated myeloperoxidase levels and the severity of coronary artery disease.  And Heslop et al. reported that elevated MPO levels more than doubled the risk for cardiovascular mortality over a 13-year period. It has also been suggested that myeloperoxidase plays a significant role in the development of the atherosclerotic lesion and rendering plaques unstable.

Medical uses 

An initial 2003 study suggested that MPO could serve as a sensitive predictor for myocardial infarction in patients presenting with chest pain. Since then, there have been over 100 published studies documenting the utility of MPO testing. The 2010 Heslop et al. study reported that measuring both MPO and CRP (C-reactive protein; a general and cardiac-related marker of inflammation) provided added benefit for risk prediction than just measuring CRP alone.

Immunohistochemical staining for myeloperoxidase used to be administered in the diagnosis of acute myeloid leukemia to demonstrate that the leukemic cells were derived from the myeloid lineage. Myeloperoxidase staining is still important in the diagnosis of myeloid sarcoma, contrasting with the negative staining of lymphomas, which can otherwise have a similar appearance. In the case of screening patients for vasculitis, flow cytometric assays have demonstrated comparable sensitivity to immunofluorescence tests, with the additional benefit of simultaneous detection of multiple autoantibodies relevant to vasculitis. Nonetheless, this method still requires further testing.

Myeloperoxidase is the first and so far only human enzyme known to break down carbon nanotubes, allaying a concern among clinicians that using nanotubes for targeted delivery of medicines would lead to an unhealthy buildup of nanotubes in tissues.

Inhibitors of MPO 

Azide has been used traditionally as an MPO inhibitor, but 4-aminobenzoic acid hydrazide (4-ABH) is a more specific inhibitor of MPO.

See also 
 Chloroma

References

External links

EC 1.11.1
Hemoproteins
골수세포형과산화효소(미엘로퍼옥시데이스, myeloperoxidase, MPO)는 인간에서 17번 염색체의 MPO 유전자에 의해 암호화되는 과산화효소이다. MPO는 백혈구의 일종인 호중구에서 가장 많이 생산되며, 항균 작용을 하기 위해 표백제에 들어간 화학 물질이기도 한 차아염소산을 만들어 낸다. 이 효소는 호중구의 아주르친화성 과립에 저장되어 있고 탈과립이 일어나면 세포밖공간으로 방출되는 리소좀 단백질이다. 호중구 골수세포형과산화효소는 점액과 가래 같은 호중구가 풍부한 분비물을 녹색으로 보이게 하는 헴 색소를 가지고 있다. 이 녹색은 효소의 옛날 이름인 'verdoperoxidase'라는 이름이 붙는 이유가 됐다.

구조 
150-kDa MPO 단백질은 2개의 15-kDa 경쇄와 2개의 무게가 가변적인, 글리코실화된 중쇄로 구성된 양이온성 이종사량체이다. 이종이량체의 동종이량체로 배열되어 칼슘 이온과 보철 헴 그룹 복합체에 결합한다. 경쇄는 글리코실화되어 있으며 변형된 철 프로토포르피린 IX 활성 자리를 포함하고 있다. 경쇄와 중쇄는 함께 Cys153에서 시스틴 다리로 연결된 두 개의 동일한 73kDa 단량체를 형성한다. 단백질은 촉매 활성을 가지는 말단 헴 공동 입구의 소수성 공간뿐만 아니라, 바닥에 헴 그룹을 보유하는 깊은 틈새를 형성한다.

중쇄의 크기만 다른 3개의 동형이 확인되었다.

리간드 중 하나는 Asp 96의 카르보닐기이다. 칼슘 결합은 촉매 활성을 가지는 His95 측쇄에 Asp 96이 매우 가깝기 때문에 활성 자리의 구조에 중요하다.

기능 
MPO는 과산화효소 XPO 서브패밀리의 구성원이며 호중구의 호흡폭발 동안 과산화 수소(H2O2)와 염화 이온(Cl-),(또는 Br-이 있는 경우 차아브롬산)으로부터 차아염소산(HOCl)을 생성한다. 이 과정에는 보조 인자로 헴이 필요하다. 또한 과산화 수소를 산화제로 사용하여 티로신을 티로실 라디칼로 산화시킨다. 차아염소산과 티로실 라디칼은 세포독성이 있어 호중구가 세균이나 기타 병원체를 죽이는 데 사용한다. 그러나 이 차아염소산은 숙주 조직에도 산화적 손상을 일으킬 수 있다. 더욱이 apoA-I이 MPO로 인해 산화되면 HDL-매개된 세포자살과 염증 억제를 감소시킨다. 또한, MPO는 단백질 니트로실화와 3-클로로티로신, 다이티로신 교차결합의 형성을 매개한다.

임상적 중요성 
골수세포형과산화효소 결핍은 유전적인 효소 결핍증으로 면역 결핍을 유발한다.

MPO에 대한 항체는 다양한 유형의 혈관염 발병에 관련되어 있으며 임상적, 병리학적으로 가장 두드러지는 세 가지 혈관염이 있다. 이들은 각각 다발성 혈관염 동반 육아종(GPA), 현미경적 다발성 혈관염(MPA), 다발성 혈관염 동반 호산구성 육아종(EGPA)이다. 항체는 항호중구 세포질 항체(ANCA)로도 알려져 있지만, ANCA는 핵 주위 영역의 염색에서도 검출되었다.

최근 연구에 따르면 골수세포형과산화효소 수치의 상승과 관상동맥질환의 중증도 사이의 연관성이 보고되었다. 및 Heslop 등은 MPO 수치가 상승하면 13년 동안 심혈관 사망 위험이 두 배 이상 증가했다고 보고했다. 또한 MPO가 죽상경화성 병변의 발달에 중요한 역할을 하고 죽종을 불안정하게 만든다는 주장도 제기되었다.

의료 목적의 사용 
2003년의 초기 연구에서는 MPO가 흉통을 호소하는 환자의 심근경색증에 대한 민감한 예측 인자로 작용할 수 있다고 제안됐다. 그 이후로 MPO 테스트의 유용성을 문서화한 100개 이상의 연구가 발표되었다. Heslop 등의 2010년 연구에 따르면 MPO와 C반응단백(CRP, 염증의 일반적인, 또는 심장 관련 표지자)를 모두 측정하면 CRP만 측정하는 것보다 위험 예측에 추가 이점이 있다고 보고했다.

백혈병 세포가 골수 계통에서 유래되었다는 것을 입증하기 위해 쓰이며, 급성 골수성 백혈병의 진단에 사용되는 골수세포성과산화효소에 대한 면역조직화학 염색이 사용된다. 골수세포성과산화효소 염색은 겉모습이 유사하게 나오는 림프종의 음성 염색과 달리 골수성육종의 진단에 여전히 중요하다. 혈관염에 대해 환자를 스크리닝하는 경우, 유세포 분석은 면역형광 검사에 가까운 민감도를 보여주었으며 혈관염과 관련된 여러 자가항체를 동시에 검출할 수 있는 추가적인 이점이 있다. 그렇지만 유세포 분석은 여전히 추가 검사가 필요하다.

골수세포형과산화효소는 탄소 나노튜브를 분해하는 것으로 알려진 최초이자, 지금까지 유일한 인간 효소이다. 의약품의 표적 전달을 위해 탄소 나노튜브를 사용하면 조직에 탄소 나노튜브가 축적되어 건강을 위협할 수 있다는 임상의의 우려를 완화해 준다.

MPO 억제제 
아자이드는 전통적으로 MPO 억제제로 사용되어 왔지만, 4-아미노벤조산 하이드라지드(4-ABH)는 MPO의 보다 특이적인 억제제이다.

참고 문헌

외부 링크 
 

헴 단백질
EC 1.11.1
인간 17번 염색체상 유전자