Methylenetetrahydrofolate reductase

MTHFR
Identifiers
AliasesMTHFR, entrez:4524, methylenetetrahydrofolate reductase
External IDsOMIM: 607093; MGI: 106639; HomoloGene: 4349; GeneCards: MTHFR; OMA:MTHFR - orthologs
Orthologs
SpeciesHumanMouse
Entrez
Ensembl
UniProt
RefSeq (mRNA)

NM_005957
NM_001330358

NM_001161798
NM_010840

RefSeq (protein)

NP_001317287
NP_005948

NP_001155270
NP_034970

Location (UCSC)Chr 1: 11.79 – 11.81 MbChr 4: 148.12 – 148.14 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

Methylenetetrahydrofolate reductase (MTHFR) is the rate-limiting enzyme in the methyl cycle, and it is encoded by the MTHFR gene.[5] Methylenetetrahydrofolate reductase catalyzes the conversion of 5,10-methylenetetrahydrofolate to 5-methyltetrahydrofolate, a cosubstrate for homocysteine remethylation to methionine. Natural variation in this gene is common in otherwise healthy people. Although some variants have been reported to influence susceptibility to occlusive vascular disease, neural tube defects, Alzheimer's disease and other forms of dementia, colon cancer, and acute leukemia, findings from small early studies have not been reproduced. Some mutations in this gene are associated with methylenetetrahydrofolate reductase deficiency.[6][7][8] Complex I deficiency with recessive spastic paraparesis has also been linked to MTHFR variants. In addition, the aberrant promoter hypermethylation of this gene is associated with male infertility and recurrent spontaneous abortion.[9][10]

Biochemistry

methylene tetrahydrofolate reductase [NAD(P)H]
Schematic diagram of the reductive carbon–nitrogen bond cleavage (represented by wavy line) catalyzed by methylenetetrahydrofolate reductase.
Identifiers
EC no.1.5.1.20
CAS no.9028-69-7
Databases
IntEnzIntEnz view
BRENDABRENDA entry
ExPASyNiceZyme view
KEGGKEGG entry
MetaCycmetabolic pathway
PRIAMprofile
PDB structuresRCSB PDB PDBe PDBsum
Gene OntologyAmiGO / QuickGO
Search
PMCarticles
PubMedarticles
NCBIproteins

In the rate-limiting step of the methyl cycle, MTHFR irreversibly reduces 5,10-methylenetetrahydrofolate (substrate) to 5-methyltetrahydrofolate (product).

MTHFR contains a bound flavin cofactor and uses NAD(P)H as the reducing agent.

Structure

Mammalian MTHFR is composed of an N-terminal catalytic domain and a C-terminal regulatory domain. MTHFR has at least two promoters and two isoforms (70 kDa and 77 kDa).[11]

Regulation

MTHFR activity may be inhibited by binding of dihydrofolate (DHF)[12] and S-adenosylmethionine (SAM, or AdoMet).[13] MTHFR can also be phosphorylated – this decreases its activity by ~20% and allows it to be more easily inhibited by SAM.[14]

Genetics

The enzyme is coded by the gene with the symbol MTHFR on chromosome 1 location p36.3 in humans.[15] There are DNA sequence variants (genetic polymorphisms) associated with this gene. In 2000 a report brought the number of polymorphisms up to 24.[16] Two of the most investigated are C677T (rs1801133) and A1298C (rs1801131) single nucleotide polymorphisms (SNPs).

While multiple published studies have drawn relationships between these SNPs and a wide variety of diseases, the American College of Medical Genetics has issued an official Practice Guideline recommending against testing or reporting on these two variants, citing "Recent meta-analyses have disproven an association between hyperhomocysteinemia and risk for coronary heart disease and between MTHFR polymorphism status and risk for venous thromboembolism. There is growing evidence that MTHFR polymorphism testing has minimal clinical utility."[17]

C677T SNP (Ala222Val)

The MTHFR nucleotide at position 677 in the gene has two possibilities: C (cytosine) or T (thymine). C at position 677 (leading to an alanine at amino acid 222) is the reference allele. The 677T allele (leading to a valine substitution at amino acid 222) encodes a thermolabile alternative enzyme variant with reduced activity. Both reference and alternative genotypes are common, with the alternative allele frequency at 10-35%, depending on ancestry.[18]

Individuals with two copies of 677C (677CC) have the most common genotype. 677TT individuals (homozygous) have lower MTHFR activity than CC or CT (heterozygous) individuals. About ten percent of the North American population are T-homozygous for this polymorphism. There is ethnic variability in the frequency of the T allele – frequency in Mediterranean/Hispanics is greater than the frequency in Caucasians which, in turn, is greater than in Africans/African-Americans.[19]

The degree of enzyme thermolability (assessed as residual activity after heat inactivation) is much greater in 677TT individuals (18–22%) compared with 677CT (56%) and 677CC (66–67%).[20] Individuals of 677TT are predisposed to mild hyperhomocysteinemia (high blood homocysteine levels), because they have less active MTHFR available to produce 5-methyltetrahydrofolate (which is used to decrease homocysteine). Low dietary intake of the vitamin folate can also cause mild hyperhomocysteinemia.

Low folate intake affects individuals with the 677TT genotype to a greater extent than those with the 677CC/CT genotypes. 677TT (but not 677CC/CT) individuals with lower plasma folate levels are at risk for elevated plasma homocysteine levels.[21] In studies of human recombinant MTHFR, the protein encoded by 677T loses its FAD cofactor three times faster than the wild-type protein.[22] 5-Methyl-THF slows the rate of FAD release in both the wild-type and mutant enzymes, although it is to a much greater extent in the mutant enzyme.[22] Low folate status with the consequent loss of FAD enhances the thermolability of the enzyme, thus providing an explanation for the normalised homocysteine and DNA methylation levels in folate-replete 677TT individuals.

This polymorphism and mild hyperhomocysteinemia are associated with neural tube defects in offspring, increased risk for complications of pregnancy other complications of pregnancy,[23] arterial and venous thrombosis, and cardiovascular disease.[24] 677TT individuals are at an increased risk for acute lymphoblastic leukemia[25] and colon cancer.[26]

Mutations in the MTHFR gene could be one of the factors leading to increased risk of developing schizophrenia.[27] Schizophrenic patients having the risk allele (T\T) show more deficiencies in executive function tasks.[28]

The C677T genotype used to be associated with increased risk of recurrent pregnancy loss (RPL) in non Caucasians,[29] however this link has been disproved in recent years.[citation needed] The American College of Medical Genetics recommendation guidelines currently state that people with recurrent pregnancy loss should not be tested for variants in the MTHFR gene.

There is also a tentative link between MTHFR mutations and dementia. One study of an elderly Japanese population[30] found correlations between the MTHFR 677CT mutation, an Apo E polymorphism, and certain types of senile dementia. Other research has found that individuals with folate-related mutations can still have a functional deficiency even when blood levels of folate are within the normal range,[31] and recommended supplementation of methyltetrahydrofolate to potentially prevent and treat dementia (along with depression). A 2011 study from China also found that the C677T SNP was associated with Alzheimer's disease in Asian populations (though not in Caucasians).[32]

C677T polymorphism is associated with risk of myocardial infarction in African, North American, and elderly populations.[33]

The CDC provides a web page with information on the "MTHFR Gene, Folic Acid, and Preventing Neural Tube Defects". National Center on Birth Defects and Developmental Disabilities, Centers for Disease Control and Prevention. 15 June 2022. Retrieved 24 Sep 2023.

A1298C SNP (Glu429Ala)

At nucleotide 1298 of the MTHFR, there are two possibilities: A or C. 1298A (leading to a Glu at amino acid 429) is the most common while 1298C (leading to an Ala substitution at amino acid 429) is less common. 1298AA is the "normal" homozygous, 1298AC the heterozygous, and 1298CC the homozygous for the "variant". In studies of human recombinant MTHFR, the protein encoded by 1298C cannot be distinguished from 1298A in terms of activity, thermolability, FAD release, or the protective effect of 5-methyl-THF.[22] The C mutation does not appear to affect the MTHFR protein. It does not result in thermolabile MTHFR and does not appear to affect homocysteine levels. It does, however, affect the conversion of MTHF to BH4 (tetrahydrobiopterin), an important cofactor in the production of neurotransmitters, and the synthesis of nitric oxide.[citation needed]

There has been some commentary on a 'reverse reaction' in which tetrahydrobiopterin (BH4) is produced when 5-methyltetrahydrofolate is converted back into methylenetetrahydrofolate. This however is not universally agreed upon. That reaction is thought to require 5-MTHF and SAMe.[citation needed] An alternative opinion is that 5-MTHF processes peroxynitrite, thereby preserving existing BH4, and that no such 'reverse reaction' occurs.

A maternal MTHFR A1298C polymorphism is associated with Down syndrome pregnancy. Subgroup and sensitivity analysis results showed that this polymorphism is a risk factor for Down syndrome pregnancy in Asian populations but not in Caucasian population as well as in overall meta-analysis.[34]

MTHFR A1298C may play a role as either a driver in the development of major depressive disorder or as a predictive or diagnostic marker, possibly in combination with C677T.[35]

Detection of MTHFR polymorphisms

A triplex tetra-primer ARMS-PCR method was developed for the simultaneous detection of C677T and A1298C polymorphisms with the A66G MTRR polymorphism in a single PCR reaction.[36]

Severe MTHFR deficiency

Severe MTHFR deficiency is rare (about 50 cases worldwide) and caused by mutations resulting in 0–20% residual enzyme activity.[16] Patients exhibit developmental delay, motor and gait dysfunction, seizures, and neurological impairment and have extremely high levels of homocysteine in their plasma and urine as well as low to normal plasma methionine levels. This deficiency and mutations in MTHFR have also been linked to recessive spastic paraparesis with complex I deficiency.[37]

A study on the Chinese Uyghur population indicated that rs1801131 polymorphism in MTHFR was associated with nsCL/P in Chinese Uyghur population. Given the unique genetic and environmental characters of the Uyghur population, these findings may be helpful for exploring the pathogenesis of this complex disease.[38]

Epigenetics

The MTHFR aberrant promoter hypermethylation is associated with male infertility. Furthermore, this improper epigenetic phenomenon was observed in semen samples of infertile males belonging to couples with a history of recurrent spontaneous abortion.[9] The MTHFR improper promoter hypermethylation may affect the two essential roles of DNA methylation in spermatogenetic cells, the global genome methylation process and the genomic imprinting of paternal genes. In addition, MTHFR gene promoter hypermethylation has also been associated with methylation loss at H19 imprinted gene in semen samples from infertile males.[10]

As a drug target

Inhibitors of MTHFR and antisense knockdown of the expression of the enzyme have been proposed as treatments for cancer.[39] The active form of folate, L-methylfolate, may be appropriate to target for conditions affected by MTHFR polymorphisms.[40]

Reaction and metabolism

The overall reaction catalyzed by MTHFR is illustrated on the right. The reaction uses an NAD(P)H hydride donor and an FAD cofactor. The E. coli enzyme has a strong preference for the NADH donor, whereas the mammalian enzyme is specific to NADPH.

MTHFR metabolism: folate cycle, methionine cycle, trans-sulfuration and hyperhomocysteinemia. 5-MTHF: 5-methyltetrahydrofolate; 5,10-methylenetetrahydrofolate; BAX: Bcl-2-associated X protein; BHMT: betaine-homocysteine S-methyltransferase; CBS: cystathionine beta synthase; CGL: cystathionine gamma-lyase; DHF: dihydrofolate (vitamin B9); DMG: dimethylglycine; dTMP: thymidine monophosphate; dUMP: deoxyuridine monophosphate; FAD+ flavine adenine dicucleotide; FTHF: 10-formyltetrahydrofolate; MS: methionine synthase; MTHFR: mehtylenetetrahydrofolate reductase; SAH: S-adenosyl-L-homocysteine; SAM (SAMe): S-adenosyl-L-methionine; THF: tetrahydrofolate.

Click on genes, proteins and metabolites below to link to respective articles.[§ 1]

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Alternative medicine

With the growth of direct-to-consumer genetic testing, the alternative medicine industry has aggressively targeted a range of dubious tests[41] and highly profitable quack treatments for claimed MTHFR polymorphisms, despite the lack of any demonstrated health effects of these mutations.[42] The promotion of supplements and other treatments for MTHFR polymorphisms, especially centered on autistic spectrum disorder,[43] have been characterised as snake oil. Tests for MTHFR, while gaining popularity, are generally unnecessary because the association of MTHFR gene mutations with various diseases have not been established as clear-cut cause-and-effect relationship.[44]

See also

References

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  2. ^ a b c GRCm38: Ensembl release 89: ENSMUSG00000029009Ensembl, May 2017
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  4. ^ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
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  21. ^ Reilly R, McNulty H, Pentieva K, Strain JJ, Ward M (February 2014). "MTHFR 677TT genotype and disease risk: is there a modulating role for B-vitamins?". The Proceedings of the Nutrition Society. 73 (1): 47–56. doi:10.1017/S0029665113003613. PMID 24131523.
  22. ^ a b c Yamada K, Chen Z, Rozen R, Matthews RG (December 2001). "Effects of common polymorphisms on the properties of recombinant human methylenetetrahydrofolate reductase". Proceedings of the National Academy of Sciences of the United States of America. 98 (26): 14853–8. Bibcode:2001PNAS...9814853Y. doi:10.1073/pnas.261469998. PMC 64948. PMID 11742092.
  23. ^ Björklund NK, Evans JA, Greenberg CR, Seargeant LE, Schneider CE, Chodirker BN (September 2004). "The C677T methylenetetrahydrofolate reductase variant and third trimester obstetrical complications in women with unexplained elevations of maternal serum alpha-fetoprotein". Reproductive Biology and Endocrinology. 2 (1): 65. doi:10.1186/1477-7827-2-65. PMC 520832. PMID 15352998.
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  26. ^ Bailey LB (November 2003). "Folate, methyl-related nutrients, alcohol, and the MTHFR 677C-->T polymorphism affect cancer risk: intake recommendations". The Journal of Nutrition. 133 (11 Suppl 1): 3748S–3753S. doi:10.1093/jn/133.11.3748S. PMID 14608109.
  27. ^ "Meta-Analysis of All Published Schizophrenia-Association Studies (Case-Control Only) for rs1801133 (C677T) polymorphism, MTHFR gene". Schizophrenia Research Forum. Archived from the original on 2012-02-09. Retrieved 2007-03-11.
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  33. ^ Alizadeh S, Djafarian K, Moradi S, Shab-Bidar S (August 2016). "C667T and A1298C polymorphisms of methylenetetrahydrofolate reductase gene and susceptibility to myocardial infarction: A systematic review and meta-analysis". International Journal of Cardiology. 217: 99–108. doi:10.1016/j.ijcard.2016.04.181. PMID 27179899.
  34. ^ Rai V, Yadav U, Kumar P (January 2017). "Null association of maternal MTHFR A1298C polymorphism with Down syndrome pregnancy: An updated meta-analysis". Egyptian Journal of Medical Human Genetics. 18 (1): 9–18. doi:10.1016/j.ejmhg.2016.04.003.
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  36. ^ Lajin B, Alachkar A, Sakur AA (February 2012). "Triplex tetra-primer ARMS-PCR method for the simultaneous detection of MTHFR c.677C>T and c.1298A>C, and MTRR c.66A>G polymorphisms of the folate-homocysteine metabolic pathway". Molecular and Cellular Probes. 26 (1): 16–20. doi:10.1016/j.mcp.2011.10.005. PMID 22074746.
  37. ^ Bathgate D, Yu-Wai-Man P, Webb B, Taylor RW, Fowler B, Chinnery PF (January 2012). "Recessive spastic paraparesis associated with complex I deficiency due to MTHFR mutations". Journal of Neurology, Neurosurgery, and Psychiatry. 83 (1): 115. doi:10.1136/jnnp.2010.218586. PMID 21131308. S2CID 13912730.
  38. ^ Xu X, Pan H, Yu L, Hong Y (2016). "Association of MTHFR polymorphisms with nsCL/P in Chinese Uyghur population". Egyptian Journal of Medical Human Genetics. 17 (4): 311–316. doi:10.1016/j.ejmhg.2016.03.003.
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Further reading

  • Overview of all the structural information available in the PDB for UniProt: P42898 (Methylenetetrahydrofolate reductase) at the PDBe-KB.

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يفتقر محتوى هذه المقالة إلى الاستشهاد بمصادر. فضلاً، ساهم في تطوير هذه المقالة من خلال إضافة مصادر موثوق بها. أي معلومات غير موثقة يمكن التشكيك بها وإزالتها. (فبراير 2023)   هذه المقالة عن اتحاد البوسنة والهرسك. لمعانٍ أخرى، طالع البوسنة والهرسك (توضيح). اتحاد البوسنة وال�...

HisnindarsyahKelompok Ahli( Pokli) RSPAL RamelanPetahanaMulai menjabat 22 April 2022PresidenJoko WidodoPanglima TNIAndika Perkasake-1Masa jabatan24 September 2019 – 26 Mei 2020 Informasi pribadiLahir11 Januari 1971 (umur 52)JakartaKebangsaan IndonesiaSuami/istriNy. Virly Mavitasari, SEAlma materSepa Prajurit Karier II (1995) Universitas Hasanuddin ( 1988-1996) Universitas Airlangga ( 2000) Universitas Patimura( 2018) STIESIA( 2021)Karier militerPihak IndonesiaDin...

هذه المقالة يتيمة إذ تصل إليها مقالات أخرى قليلة جدًا. فضلًا، ساعد بإضافة وصلة إليها في مقالات متعلقة بها. (نوفمبر 2019) أليكس ليندسي   معلومات شخصية الميلاد 10 يوليو 1971 (52 سنة)  مواطنة الولايات المتحدة  الحياة العملية المهنة مدون صوتي  المواقع IMDB صفحته على IMDB  تعديل...

U.S. activists Street Riders NYCPart of Black Lives Matter, George Floyd protestsDateFormed in June 2020LocationNew York CityCaused by Justice for George Floyd Justice for Breonna Taylor Justice for Ahmaud Arbery Criminal justice reform in the United States Police brutality in the United States Racism against people of color in America including immigrants 8 minutes and 46 seconds of silence for George Floyd at Battery Park during a protest led by Street Riders NYC on June 20, 2020 Street Rid...

Death Times Three AuthorRex StoutCountryUnited statesLanguageEnglishSeriesNero WolfeGenreDetective fictionPublisherBantam BooksPublication dateDecember 1985Media typePrint (paperback)Pages213 pp. (first edition)ISBN0-553-25425-1OCLC12853382Preceded byA Family Affair  Death Times Three is a collection of Nero Wolfe novellas by Rex Stout, published posthumously by Bantam Books in 1985. It is the only collection of Stout's Nero Wolfe stories not to have appeared first in hardcover...

U.S. House district for Connecticut CT-5 redirects here. The term may also refer to U.S. Route 5 in Connecticut. Connecticut's 5th congressional districtInteractive map of district boundaries since January 3, 2023Representative  Jahana HayesD–WolcottArea1,282 sq mi (3,320 km2)Distribution85.79% urban14.21% ruralPopulation (2022)734,438Median householdincome$87,715[1]Ethnicity70.9% White16.8% Hispanic6.5% Black3.6% Asian1.6% Two or more races0.6% otherCook PVID+3&...

Artikel ini tidak memiliki referensi atau sumber tepercaya sehingga isinya tidak bisa dipastikan. Tolong bantu perbaiki artikel ini dengan menambahkan referensi yang layak. Tulisan tanpa sumber dapat dipertanyakan dan dihapus sewaktu-waktu.Cari sumber: Barang – berita · surat kabar · buku · cendekiawan · JSTOR Barang atau komoditas dalam pengertian ekonomi adalah suatu objek fisik yang dapat dilihat dan disimpan atau jasa yang memiliki nilai. Nilai sua...

Citizen FilmTypeNonprofitIndustryDocumentary, Film, New Media, StorytellingFoundedSan Francisco, California (2002)HeadquartersSan Francisco, CA, United StatesKey peopleSam BallSophie ConstantinouKate Stilley SteinerWebsitehttps://citizenfilm.org Citizen Film is a San Francisco-based documentary company founded in 2002 by Sam Ball, Sophie Constantinou and Kate Stilley Steiner. Documentaries They produce long-form documentary programs such as Joann Sfar Draws from Memory and Green Streets (in p...

American businessman Richard EdelmanEdelman in 2011BornRichard Winston EdelmanJune 1954 (age 69)Chicago, Illinois, U.S.EducationPhillips Exeter Academy Harvard University (AB) Harvard Business School (MBA)TitlePresident and CEO, EdelmanTerm1996–Spouses Rosalind Anne Walrath ​ ​(m. 1986; div. 2015)​ Claudia Romo González ​ ​(m. 2017)​ Children3Parent(s)Daniel Edelman Ruth Ann RozumoffWebsiteRichard ...

Not to be confused with City of Industry or Industrial city. Historic intermodal shipping, warehousing, and manufacturing complex in Brooklyn, New York Bush Terminal in 1958, looking north, with Lower Manhattan in the distance Location in New York City Industry City (also Bush Terminal)[a] is a historic intermodal shipping, warehousing, and manufacturing complex on the Upper New York Bay waterfront in the Sunset Park neighborhood of Brooklyn, New York City. The northern portion, commo...

Batalyon Infanteri Raider Khusus 753/Arga Vira TamaLambang Yonif 753/Arga Vira TamaDibentuk17 Februari 1970NegaraIndonesiaCabangInfanteri RaiderTipe unitSatuan TempurBagian dariKorem 173/Praja Vira BrajaMarkasNabire, Papua TengahJulukanKsatria Walet HitamMotoArga Vira TamaBaretHijau LumutMaskotBurung Walet HitamUlang tahun17 Februari Batalyon Infanteri Raider Khusus 753/Arga Vira Tama atau Yonif RK 753/AVT adalah sebuah batalyon infanteri Tentara Nasional Indonesia (TNI) yang berada di bawah ...

Martin EdenMartin Eden (Luca Marinelli) in una scena del filmLingua originaleitaliano Paese di produzioneItalia, Francia Anno2019 Durata129 minuti Rapporto1,66:1 Generedrammatico, sentimentale, storico RegiaPietro Marcello SoggettoJack London (romanzo) SceneggiaturaMaurizio Braucci, Pietro Marcello ProduttorePietro Marcello, Beppe Caschetto, Thomas Ordonneau, Michael Weber, Viola Fügen Produttore esecutivoDario Zonta, Alessio Lazzareschi, Michel Merkt Casa di produzioneAvventuros...

This article relies largely or entirely on a single source. Relevant discussion may be found on the talk page. Please help improve this article by introducing citations to additional sources.Find sources: Battle of Coille Bhan – news · newspapers · books · scholar · JSTOR (September 2014) Battle of Coille BhanPart of the aftermath of the Jacobite rising of 1719Attadale ForestDate1721LocationAttadale, Scotland, Great BritainResult Tactical Government vi...

American politician David Marston Clough13th Governor of MinnesotaIn officeJanuary 31, 1895 – January 2, 1899LieutenantFrank A. DayJohn L. GibbsPreceded byKnute NelsonSucceeded byJohn Lind12th Lieutenant Governor of MinnesotaIn officeJanuary 9, 1893 – January 31, 1895GovernorKnute NelsonPreceded byGideon S. IvesSucceeded byFrank A. DayMember of the Minnesota SenateIn office1887-1893 Personal detailsBorn(1846-12-27)December 27, 1846Lyme, New Hampshire, U.S.DiedAug...

Villar de Santos San Xoán de Vilar de Santos parroquia de Galicia Villar de SantosUbicación de Villar de Santos en España. Villar de SantosUbicación de Villar de Santos en la provincia de Orense.País  España• Com. autónoma  Galicia• Provincia  Orense• Comarca La Limia• Municipio Villar de SantosUbicación 42°05′15″N 7°47′41″O / 42.087475, -7.7948111111111• Altitud 643 metrosPoblación 4...

Kampanye GuadalkanalBagian dari Perang Pasifik Perang Dunia IIFoto Marinir Amerika Serikat sedang beristirahat selama Pertempuran Guadalkanal, November 1942, kemungkinan mereka berasal dari Divisi 2 Marinir.Tanggal7 Agustus 1942–9 Februari 1943LokasiGuadalkanal di Kepulauan SolomonHasil Kemenangan strategis SekutuPihak terlibat Pihak Sekutu yang terdiri dari: Amerika Serikat Australia Selandia Baru Kepulauan Solomon Britania[1] Tonga[2] Fiji[3] &#...

Outdoor football stadium in Fresno, California, USA Bulldog Stadium redirects here. For the stadium at Bryant University, see Beirne Stadium. For the stadium at Bowie State University, see Bulldogs Stadium. Valley Children’s StadiumThe DoghouseView from northeast in October 2012FresnoLocation in the United StatesShow map of the United StatesFresnoLocation in CaliforniaShow map of CaliforniaFormer namesBulldog Stadium(1980–2021)Address1620 E Bulldog LaneLocationFresno, California, U.S.Coor...