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Asam beta-hidroksi beta-metilbutirat

senyawa kimia
Artikel ini bukan mengenai asam β-hidroksibutirat.

Asam β-hidroksi β-metilbutirat[catatan 1] (HMB), atau yang dikenal dengan basa konjugatnya, β-hidroksi β-metilbutirat, adalah suatu senyawa yang dihasilkan secara alami dalam tubuh manusia yang digunakan sebagai suplemen makanan serta sebagai bahan dalam beberapa makanan medis yang diperuntukkan bagi penyembuhan luka serta menyediakan dukungan nutrisi bagi individu dengan atrofi otot akibat kanker atau HIV/AIDS.[sumber 1] Pada orang dewasa yang sehat, suplementasi dengan HMB telah terbukti meningkatkan ukuran otot yang diinduksi olahraga, kekuatan otot, dan perampingan massa tubuh, mengurangi kerusakan otot rangka saat olahraga, meningkatkan latihan kinerja aerobik, dan mempercepat pemulihan dari olahraga.[sumber 2] Tinjauan medis dan meta-analisis menunjukkan bahwa suplementasi HMB juga membantu menjaga atau meningkatkan massa tubuh dan kekuatan otot pada individu yang mengalami kehilangan otot akibat usia.[catatan 2][11][12][13] HMB menghasilkan efek ini sebagian dengan merangsang produksi protein dan menghambat pemecahan protein di jaringan otot.[11][14][15] Tidak ada efek samping dari penggunaan jangka panjang senyawa ini sebagai suplemen makanan pada orang dewasa yang telah ditemukan.[16][17][18]

asam β-hidroksi β-metilbutirat
Rumus struktur, asam konjugasi
Rumus struktur, basa konjugasi
Atas: Asam β-hidroksi β-metilbutirat
Bawah: β-hidroksi β-metilbutirat
Nama sistematis (IUPAC)
asam 3-hidroksi-3-metilbutanoat
Data klinis
Kat. kehamilan ?
Status hukum ? (US)
Rute Oral[1] atau nasogastris[2]
Data farmakokinetik
Waktu paruh HMB-FA: 3 jam[1]
HMB-Ca: 2.5 jam[1]
Ekskresi Ginjal (10–40% diekskresikan)[1][3]
Pengenal
Nomor CAS 625-08-1 YaY
Kode ATC None
PubChem CID 69362
ChemSpider 62571 YaY
UNII 3F752311CD YaY
KEGG C20827 YaY
ChEBI CHEBI:37084 YaY
Sinonim Bentuk asam konjugasi:
asam β-hidroksiisovalerat
asam 3-hidroksiisovalerat
Bentuk basa konjugasi:
hidroksimetilbutirat
Data kimia
Rumus C5H10O3 

  • InChI=1S/C5H10O3/c1-5(2,8)3-4(6)7/h8H,3H2,1-2H3,(H,6,7) YaY
    Key:AXFYFNCPONWUHW-UHFFFAOYSA-N YaY

Data fisik
Kepadatan ~1.1 g/cm³
Titik lebur −80 °C (-112 °F) (kaca)[4]
Titik didih 128 °C (262 °F) pada 7 mmHg[5][6]

Penggunaan

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Bentuk yang tersedia

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HMB dijual sebagai suplemen makanan yang dijual bebas dalam bentuk asam bebasnya, asam β-hidroksi β-metilbutirat (HMB-FA), dan sebagai garam kalsium monohidrat dari basa konjugatnya, kalsium β-hidroksi β-metilbutirat monohidrat (HMB-Ca, CaHMB).[19][20] Karena hanya sebagian kecil dari prekursor metabolisme HMB, L-leusin, dimetabolisme menjadi HMB, konsentrasi aktif senyawa dalam plasma darah dan otot hanya dapat dicapai dengan menambahkan HMB secara langsung.[1][21][22] Orang dewasa yang sehat menghasilkan sekitar 0.3 gram per hari, sedangkan HMB tambahan biasanya dikonsumsi dalam dosis 3–6 gram per hari.[17] HMB dijual dengan harga sekitar US$30–50 per bulan ketika dikonsumsi dengan dosis 3 gram per hari.[16] HMB juga terkandung dalam beberapa produk nutrisi dan makanan medis yang dipasarkan oleh Abbott Laboratories (sepeti, formulasi tertentu Goldsure, Juven, dan Myoplex),[8][23] serta hadir dalam jumlah yang tidak signifikan dalam makanan tertentu, seperti alfalfa, asparagus, alpukat, kembang kol, limau gedang, dan ikan lele.[24][25]

Kedokteran

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HMB tambahan telah digunakan dalam uji klinis sebagai pengobatan untuk menjaga massa tubuh tanpa lemak dalam kondisi pengecilan otot, khususnya sarkopenia, dan telah dipelajari dalam uji klinis sebagai terapi tambahan bersamaan dengan latihan ketahanan.[11][16][21] Berdasarkan dua ulasan medis dan meta-analisis dari tujuh uji acak terkendali, suplementasi HMB dapat mempertahankan atau meningkatkan massa otot dan kekuatan otot pada orang dewasa yang lebih tua.[catatan 2][11][12][13]

Beberapa produk bermerek yang mengandung HMB (yaitu, formulasi tertentu dari Ensure dan Juven) merupakan makanan medis yang dimaksudkan untuk digunakan untuk memberikan dukungan nutrisi di bawah perawatan dokter pada individu dengan atrofi otot akibat HIV/AIDS atau kanker, untuk mempromosikan penyembuhan luka setelah pembedahan atau cedera, atau ketika direkomendasikan oleh profesional medis.[sumber 3]

Peningkatan performa

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Dengan program olahraga yang tepat, suplementasi makanan dengan 3 gram HMB per hari telah terbukti meningkatkan peningkatan ukuran otot yang diinduksi oleh olahraga, kekuatan dan ketahanan otot, dan massa tubuh tanpa lemak, mengurangi kerusakan otot rangka yang disebabkan oleh olahraga,[catatan 3] dan mempercepat pemulihan dari latihan dengan intensitas tinggi.[sumber 2]

Farmakologi

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Farmakodinamika

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Beberapa komponen kaskade persinyalan yang memediasi peningkatan yang diinduksi oleh HMB dalam sintesis protein otot rangka manusia telah diidentifikasi secara in vivo.[14][15]

Biosintesis

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Mayoritas metabolisme L-leusin mulanya dikatalisis oleh enzim asam amino rantai samping aminotransferase, menghasilkan α-ketoisokaproat (α-KIC).[3][28] α-KIC utamanya dimetabolisme oleh enzim mitokondrial asam α-keto rantai cabang dehidrogenase, yang mengubahnya menjadi isovaleril-CoA.[3][28] Isovaleril-KoA selanjutnya dimetabolisme oleh isovaleril-KoA dehidrogenase dan dikonversi menjadi MC-KoA, yang digunakan dalam sintesis asetil-KoA dan senyawa lainnya.[28] Selama defisiensi biotin, HMB dapat disintesis dari MC-KoA melalui enoil-KoA hidratase dan enzim tioesterase yang tidak diketahui,[29][30][31] yang mengubah MC-KoA menjadi HMB-KoA dan HMB-KoA menjadi HMB berturut-turut.[30] Sejumlah kecil α-KIC dimetabolisme di hati oleh enzim sitosolik 4-hidroksifenilpiruvat dioksigenase (KIC dioksigenase), yang mengubah α-KIC menjadi HMB.[3][28][32] Pada individu sehat, jalur minor ini – yang melibatkan konversi L-leusin menjadi α-KIC dan kemudian HMB – adalah jalur utama sintesis HMB.[3][28]

Efek samping

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Profil keamanan HMB pada manusia dewasa didasarkan pada bukti dari uji klinis pada manusia dan penelitian pada hewan.[16][18] Pada manusia, tidak ada efek samping pada orang dewasa muda atau orang dewasa yang lebih tua yang telah dilaporkan ketika HMB dikonsumsi dalam dosis 3 gram per hari hingga satu tahun.[16][17][18]

Kimia

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Rumus kerangka asam butirat dengan karbon alfa, beta, dan gamma ditandai
 
Rumus asam β-hidroksi β-metilbutirat

Asam β-hidroksi β-metilbutirat adalah suatu asam β-hidroksi monokarboksilat serta produk alami dengan rumus molekul C5H10O3.[33][34] Pada suhu ruangan, asam β-hidroksi β-metilbutirat terdapat sebagai cairan transparan, tak berwarna hingga kuning terang yang larut dalam air.[6][35][36] Asam β-hidroksi β-metilbutirat adalah suatu asam lemah dengan pKa 4.4.[4] Indeks refraksi ( ) senyawa ini adalah 1.42.[4]

Struktur kimia

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Asam β-hidroksi β-metilbutirat merupakan anggota keluarga senyawa organik asam karboksilat.[33] Senyawa ini adalah analog struktural dari asam butirat dengan gugus fungsi hidroksil dan suatu substituen metil yang berlokasi pada karbon beta.[33][37] Dengan perpanjangan, analog struktur lainnya diantaranya asam β-hidroksibutirat dan asam β-metilbutirat.[33][37]

Sintesis

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Berbagai jalur sintesis asam β-hidroksi β-metilbutirat telah dikembangkan. Pendekatan sintesis kimia HMB yang pertama dilaporkan mendekati HMB dengan oksidasi alkena, diol visinal, dan prekursor alkohol:

  • pada tahun 1877, kimiawan Rusia Michael dan Alexander Zaytsev melaporkan preparasi HMB oleh oksidasi 2-metilpent-4-en-2-ol dengan asam kromat (H2CrO4);[38]
  • pada tahun 1880 dan 1889, Schirokoff dan Reformatsky (masing-masing) melaporkan bahwa pembelahan oksidatif diol visinal 4-metilpentana-1,2,4-triol dengan kalium permanganat (KMnO4) dalam suasana asam menghasilkan HMB[39][40] – hasil ini paling mendekati terkait dengan sintesis pertama karena KMnO4 encer dan dingin mengoksidasi alkena menjadi diol-cis visinal yang lebih lanjut dioksidasi oleh KMnO4 panas dalam suasana asam menjadi senyawa yang mengandung karbonil, serta zat antara diol tidak diperoleh kita kondisi asam dan panas digunakan bagi oksidasi alkena.[41] Dengan kata lain, rasemat 4-metilpentana-1,2,4-triol adalah turunan 2-metilpent-4-en-2-ol dan asam β-hidroksi β-metilbutirat adalah turunan keduanya; serta,
  • pada tahun 1892, Kondakow melaporkan preparasi HMB oleh oksidasi 3-metilbutana-1,3-diol dengan permanganat.[42]
 
Jalur sintesis asam β-hidroksi β-metilbutirat pertama

Bergantung pada kondisi eksperimen, sikloadisi dari aseton dan ketena menghasilkan β-isovalerolakton atau 4,4-dimetiloksetan-2-on,[43][44] keduanya terhidrolisis dalam kondisi basa untuk menghasilkan basa konjugat dari HMB. Reaksi haloform menyediakan jalur lain ke HMB yang melibatkan halogenasi lengkap dari wilayah metil-keton alkohol diaseton dengan natrium hipobromit atau natrium hipoklorit;[4][45][46]

Catatan

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  1. ^ Sinonim dan ejaan lain termasuk: asam beta-hidroksi beta-metilbutirat, asam 3-hidroksi-3-metilbutanoat (nama IUPAC), asam 3-hidroksiisovalerat, dan asam beta-hidroksiisovalerat.[7]
  2. ^ a b Meta-analisis menemukan bahwa peningkatan rata-rata massa otot akibat suplementasi HMB pada orang dewasa yang lebih tua adalah 035 kilogram (77 pon).[11] Dengan selang kepercayaan 95% untuk perkiraan peningkatan massa otot karena suplementasi HMB sebesar 011–059 kilogram (24–130 pon).[11]
    Tujuh uji acak terkendali yang dimasukkan dalam meta-analisis berisi total 147 orang dewasa yang lebih tua dalam kelompok perlakuan HMB dan 140 orang dewasa yang lebih tua dalam kelompok kontrol.[11] Tujuh uji berdurasi 2–11 bulan dan durasi rata-rata studi ini, ditimbang dengan ukuran sampel, sekira 6 bulan.[11]
  3. ^ Efek HMB pada kerusakan otot rangka telah dinilai dalam penelitian pada manusia menggunakan empat biomarker berbeda dari kerusakan otot atau pemecahan protein: serum kreatin kinase, serum laktat dehidrogenase, nitrogen urea urin, and 3-metilhistidin urin.[1][19][26] Ketika intensitas dan volume latihan cukup untuk menyebabkan kerusakan otot rangka, seperti selama lari jarak jauh atau kelebihan beban progresif, suplementasi HMB telah ditunjukkan untuk melemahkan peningkatan biomarker ini sebesar 20–60%.[1][19][27]

Catatan referensi

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  1. ^ [1][8][9][10]
  2. ^ a b [1][11][12][14][19][26][27]
  3. ^ [2][8][9][10]

Referensi

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  1. ^ a b c d e f g h i Wilson JM, Fitschen PJ, Campbell B, Wilson GJ, Zanchi N, Taylor L, Wilborn C, Kalman DS, Stout JR, Hoffman JR, Ziegenfuss TN, Lopez HL, Kreider RB, Smith-Ryan AE, Antonio J (February 2013). "International Society of Sports Nutrition Position Stand: beta-hydroxy-beta-methylbutyrate (HMB)". Journal of the International Society of Sports Nutrition. 10 (1): 6. doi:10.1186/1550-2783-10-6. PMC 3568064  . PMID 23374455. The [International Society of Sports Nutrition] has concluded the following. 1. HMB can be used to enhance recovery by attenuating exercise induced skeletal muscle damage in trained and untrained populations. ... 4. Thirty-eight mg·kg·BM−1 daily of HMB has been demonstrated to enhance skeletal muscle hypertrophy, strength, and power in untrained and trained populations when the appropriate exercise prescription is utilized. ... 8. HMB’s mechanisms of action include an inhibition and increase of proteolysis and protein synthesis, respectively. 9. Chronic consumption of HMB is safe in both young and old populations. 
  2. ^ a b "Product Information: Ensure Enlive Advanced Therapeutic Nutrition Shake" (PDF). Abbott Nutrition. 9 August 2016. Diarsipkan (PDF) dari versi asli tanggal 12 October 2016. Diakses tanggal 22 August 2016.
     • Use under medical supervision.
     • HMB + protein for muscle health.     

    "Product Information: Juven" (PDF). Abbott Nutrition. 7 May 2016. Diarsipkan (PDF) dari versi asli tanggal 12 October 2016. Diakses tanggal 22 August 2016.
     • Administer orally or as a modular via feeding tube ...
     • Use under medical supervision.
     • Nutravigor® (CaHMB, calcium β-hydroxy-β-methylbutyrate)     
  3. ^ a b c d Coffman DD, Cramer R, Mochel WE (June 1958). "Syntheses by Free-radical Reactions. V. A New Synthesis of Carboxylic Acids". Journal of the American Chemical Society. 80 (11): 2882–2887. doi:10.1021/ja01544a072. 
  4. ^ "Safety data sheet: 3-Hydroxy-3-methyl butyric acid". Alfa Aesar. 23 March 2005. Diarsipkan dari versi asli tanggal 17 September 2016. Diakses tanggal 9 November 2016. 
  5. ^ a b "3-OH-isovaleric acid". ChemSpider. Royal Society of Chemistry. 2015. Diarsipkan dari versi asli tanggal 11 August 2016. Diakses tanggal 10 August 2016. Experimental Boiling Point: ... 128 °C / 7 mm ...
    Experimental solubility:
    Soluble in water     
  6. ^ "beta-Hydroxyisovaleric acid". PubChem Compound. United States National Library of Medicine – National Center for Biotechnology Information. 3 February 2018. Diarsipkan dari versi asli tanggal 6 February 2018. Diakses tanggal 6 February 2018. Chemical Names: Beta-Hydroxyisovaleric acid; 3-Hydroxy-3-methylbutanoic acid; ... 3-Hydroxyisovaleric acid; 3-Hydroxy-3-methylbutyric acid 
  7. ^ a b c Linn J (13 May 2013). "Proteins in Human Health and Performance". Iowa State University. Diarsipkan dari versi asli tanggal 27 August 2016. Diakses tanggal 31 July 2016. Dr. Nissen and his collaborator Dr. Naji N. Abumrad, Professor and Chair, Department of Surgery, Vanderbilt University, discovered beta-hydroxy-beta-methylbutyrate (HMB) and its beneficial effects on human health and performance. HMB is currently marketed nationally by Abbott Laboratories as Revigor™, which is a component of Goldsure® Muscle Health, and Juven®, which is a nutritional beverage that is clinically shown to promote healing after injury or surgery. 
  8. ^ a b Khamsi R (May 2013). "Rethinking the formula". Nature Medicine. 19 (5): 525–529. doi:10.1038/nm0513-525. PMID 23652097. The questions about what defines a medical food will likely grow as the market does—and that market now extends far beyond PKU and other inherited metabolic disorders. ... Abbott Nutrition's Juven provides nutrients to people with HIV or AIDS experiencing excessive weight loss due to disease 
  9. ^ a b "JUVEN Added to Abbott Laboratories' Nutritional Product Line for People With Cancer, HIV/AIDS and Wounds/Pressure Ulcers". PR Newswire. Abbott Laboratories. 12 March 2004. Diarsipkan dari versi asli tanggal 20 December 2016. Diakses tanggal 11 December 2016. 
  10. ^ a b c d e f g h i Wu H, Xia Y, Jiang J, Du H, Guo X, Liu X, Li C, Huang G, Niu K (September 2015). "Effect of beta-hydroxy-beta-methylbutyrate supplementation on muscle loss in older adults: a systematic review and meta-analysis". Archives of Gerontology and Geriatrics. 61 (2): 168–175. doi:10.1016/j.archger.2015.06.020. PMID 26169182. Overall, this meta-analysis indicates that HMB can prevent lean body mass loss in older adults. But the effects of HMB on muscle strength and physical function appears to vary in different populations. Additional well-designed clinical studies are necessary to confirm the effectiveness of HMB in the prevention of loss of muscle strength and physical function. ... Mechanisms underlying the role of HMB in muscle regeneration have also been explored: results indicated that HMB enhances protein synthesis via upregulation of anabolic signaling pathways and attenuate proteolysis via downregulation of catabolic signaling pathways (Wilkinson et al., 2013). 
  11. ^ a b c Holeček M (August 2017). "Beta-hydroxy-beta-methylbutyrate supplementation and skeletal muscle in healthy and muscle-wasting conditions". Journal of Cachexia, Sarcopenia and Muscle. 8 (4): 529–541. doi:10.1002/jcsm.12208. PMC 5566641  . PMID 28493406. The reports summarized here indicate that HMB provides a number of benefits to subjects involved in strength-power and endurance sports. The effects on muscle mass and strength, particularly during resistance training, are likely related to the suppression of proteolysis and a positive effect on protein synthesis. Its benefits in aerobic performance are probably more associated with improved mitochondrial biogenesis and fat oxidation. Favourable effects on the recovery from exercise-induced damage may be related to the role of HMB as a precursor of cholesterol, which modulates membrane fluidity and affects ion channels, and membrane excitability. ... Studies have demonstrated that HMB can prevent the development of sarcopenia in elderly subjects and that the optimal action of HMB on muscle growth and strength occurs when it is combined with exercise. 
  12. ^ a b Rossi AP, D'Introno A, Rubele S, Caliari C, Gattazzo S, Zoico E, Mazzali G, Fantin F, Zamboni M (October 2017). "The Potential of β-Hydroxy-β-Methylbutyrate as a New Strategy for the Management of Sarcopenia and Sarcopenic Obesity". Drugs & Aging. 34 (11): 833–840. doi:10.1007/s40266-017-0496-0. PMID 29086232. Clinical trials performed in older adults confirm that HMB can attenuate the progression of sarcopenia in elderly subjects. HMB supplementation results in an increase in skeletal muscle mass and strength in the elderly and its effect is even greater when combined with physical exercise. 
  13. ^ a b c Silva VR, Belozo FL, Micheletti TO, Conrado M, Stout JR, Pimentel GD, Gonzalez AM (September 2017). "β-hydroxy-β-methylbutyrate free acid supplementation may improve recovery and muscle adaptations after resistance training: a systematic review". Nutrition Research. 45: 1–9. doi:10.1016/j.nutres.2017.07.008. PMID 29037326. HMB's mechanisms of action are generally considered to relate to its effect on both muscle protein synthesis and muscle protein breakdown (Figure 1) [2, 3]. HMB appears to stimulate muscle protein synthesis through an up-regulation of the mammalian/mechanistic target of rapamycin complex 1 (mTORC1), a signaling cascade involved in coordination of translation initiation of muscle protein synthesis [2, 4]. Additionally, HMB may have antagonistic effects on the ubiquitin–proteasome pathway, a system that degrades intracellular proteins [5, 6]. Evidence also suggests that HMB promotes myogenic proliferation, differentiation, and cell fusion [7]. ... Exogenous HMB-FA administration has shown to increase intramuscular anabolic signaling, stimulate muscle protein synthesis, and attenuate muscle protein breakdown in humans [2]. 
  14. ^ a b Wilkinson DJ, Hossain T, Hill DS, Phillips BE, Crossland H, Williams J, Loughna P, Churchward-Venne TA, Breen L, Phillips SM, Etheridge T, Rathmacher JA, Smith K, Szewczyk NJ, Atherton PJ (June 2013). "Effects of leucine and its metabolite β-hydroxy-β-methylbutyrate on human skeletal muscle protein metabolism". The Journal of Physiology. 591 (11): 2911–2923. doi:10.1113/jphysiol.2013.253203. PMC 3690694  . PMID 23551944. The stimulation of MPS through mTORc1-signalling following HMB exposure is in agreement with pre-clinical studies (Eley et al. 2008). ... Furthermore, there was clear divergence in the amplitude of phosphorylation for 4EBP1 (at Thr37/46 and Ser65/Thr70) and p70S6K (Thr389) in response to both Leu and HMB, with the latter showing more pronounced and sustained phosphorylation. ... Nonetheless, as the overall MPS response was similar, this cellular signalling distinction did not translate into statistically distinguishable anabolic effects in our primary outcome measure of MPS. ... Interestingly, although orally supplied HMB produced no increase in plasma insulin, it caused a depression in MPB (−57%). Normally, postprandial decreases in MPB (of ~50%) are attributed to the nitrogen-sparing effects of insulin since clamping insulin at post-absorptive concentrations (5 μU ml−1) while continuously infusing AAs (18 g h−1) did not suppress MPB (Greenhaff et al. 2008), which is why we chose not to measure MPB in the Leu group, due to an anticipated hyperinsulinaemia (Fig. 3C). Thus, HMB reduces MPB in a fashion similar to, but independent of, insulin. These findings are in-line with reports of the anti-catabolic effects of HMB suppressing MPB in pre-clinical models, via attenuating proteasomal-mediated proteolysis in response to LPS (Eley et al. 2008). 
  15. ^ a b c d e Brioche T, Pagano AF, Py G, Chopard A (August 2016). "Muscle wasting and aging: Experimental models, fatty infiltrations, and prevention". Molecular Aspects of Medicine. 50: 56–87. doi:10.1016/j.mam.2016.04.006. PMID 27106402. In conclusion, HMB treatment clearly appears to be a safe potent strategy against sarcopenia, and more generally against muscle wasting, because HMB improves muscle mass, muscle strength, and physical performance. It seems that HMB is able to act on three of the four major mechanisms involved in muscle deconditioning (protein turnover, apoptosis, and the regenerative process), whereas it is hypothesized to strongly affect the fourth (mitochondrial dynamics and functions). Moreover, HMB is inexpensive (~30– 50 US dollars per month at 3 g per day) and may prevent osteopenia (Bruckbauer and Zemel, 2013; Tatara, 2009; Tatara et al., 2007, 2008, 2012) and decrease cardiovascular risks (Nissen et al., 2000). For all these reasons, HMB should be routinely used in muscle-wasting conditions especially in aged people. ... 3 g of CaHMB taken three times a day (1 g each time) is the optimal posology, which allows for continual bioavailability of HMB in the body (Wilson et al., 2013) 
  16. ^ a b c Molfino A, Gioia G, Rossi Fanelli F, Muscaritoli M (December 2013). "Beta-hydroxy-beta-methylbutyrate supplementation in health and disease: a systematic review of randomized trials". Amino Acids. 45 (6): 1273–1292. doi:10.1007/s00726-013-1592-z. PMID 24057808. Normally, an individual metabolizes 60 g of L-LEU to obtain 3 g of HMB but a 70 kg person produces 0.2–0.4 g of HMB per day, depending on the dose of LEU in the diet (Van Koevering and Nissen 1992). ... The usual dose of 3 g/day may be routinely recommended to maintain or improve muscle mass and function in health and disease. The safety profile of HMB is unequivocal. ... These results show that HMB/ARG/GLN can be safely used to treat AIDS- and cancer-related muscle wasting 
  17. ^ a b c Borack MS, Volpi E (December 2016). "Efficacy and Safety of Leucine Supplementation in the Elderly". The Journal of Nutrition. 146 (12): 2625S–2629S. doi:10.3945/jn.116.230771. PMC 5118760  . PMID 27934654. One study tested the safety of HMB for long-term use in rats. Fuller et al. (50) conducted a 91-d study with the use of Sprague-Dawley rats that tested the safety of β-hydroxy-β-methylbutyric free acid (HMBFA). This new form of HMB results in higher HMB serum concentrations than CaHMB. In this study, rats were administered an HMBFA intervention of 0%, 0.8%, 1.6%, or 4% of the diet by body weight. The highest dose is the equivalent of ~400 mg ⋅ kg−1 ⋅ d−1 for humans. No adverse advents were observed for any treatment group. Similarly, blood and urine analyses were within the normal range in all groups, with no group differences. The authors concluded that HMBFA was safe for consumption in a rat model. ... No serious side effects have been reported with leucine, EAA, or HMB supplementation; and the health risks associated with these supplements are few and predictable. 
  18. ^ a b c d Momaya A, Fawal M, Estes R (April 2015). "Performance-enhancing substances in sports: a review of the literature". Sports Medicine. 45 (4): 517–531. doi:10.1007/s40279-015-0308-9. PMID 25663250. Currently, HMB is available as an over-the-counter supplement. The drug is not tested for nor banned by any sporting organization. ... Wilson et al. [91] demonstrated that when non-resistance trained males received HMB pre-exercise, the rise of lactate dehydrogenase (LDH) levels reduced, and HMB tended to decrease soreness. Knitter et al. [92] showed a decrease in LDH and creatine phosphokinase (CPK), a byproduct of muscle breakdown, by HMB after a prolonged run. ... The utility of HMB does seem to be affected by timing of intake prior to workouts and dosage [97]. Further, chronic consumption of HMB appears safe [97]. ... No serious adverse effects from HMB consumption have been reported. 
  19. ^ Fuller JC, Sharp RL, Angus HF, Khoo PY, Rathmacher JA (November 2015). "Comparison of availability and plasma clearance rates of β-hydroxy-β-methylbutyrate delivery in the free acid and calcium salt forms". primary source. The British Journal of Nutrition. 114 (9): 1403–1409. doi:10.1017/S0007114515003050. PMID 26373270. Recently, the free acid form of HMB (HMB-FA) has become commercially available in capsule form (gelcap). The current study was conducted to compare the bioavailability of HMB using the two commercially available capsule forms of HMB-FA and Ca-HMB. ... In conclusion, HMB-FA in capsule form improves clearance rate and availability of HMB compared with Ca-HMB in capsule form. 
  20. ^ a b Argilés JM, Campos N, Lopez-Pedrosa JM, Rueda R, Rodriguez-Mañas L (September 2016). "Skeletal Muscle Regulates Metabolism via Interorgan Crosstalk: Roles in Health and Disease". Journal of the American Medical Directors Association. 17 (9): 789–796. doi:10.1016/j.jamda.2016.04.019. PMID 27324808. Studies suggest dietary protein and leucine or its metabolite β-hydroxy β-methylbutyrate (HMB) can improve muscle function, in turn improving functional performance. ... These have identified the leucine metabolite β-hydroxy β-methylbutyrate (HMB) as a potent stimulator of protein synthesis as well as an inhibitor of protein breakdown in the extreme case of cachexia. ... A growing body of evidence suggests HMB may help slow, or even reverse, the muscle loss experienced in sarcopenia and improve measures of muscle strength. ... However, dietary leucine does not provide a large amount of HMB: only a small portion, as little as 5%, of catabolized leucine is metabolized into HMB. ... Thus, although dietary leucine itself can lead to a modest stimulation of protein synthesis by producing a small amount of HMB, direct ingestion of HMB more potently affects such signaling, resulting in demonstrable muscle mass accretion. ... Indeed, a vast number of studies have found that supplementation of HMB to the diet may reverse some of the muscle loss seen in sarcopenia and in hypercatabolic disease. ... The overall treatment of muscle atrophy should include dietary supplementation with HMB, although the optimal dosage for each condition is still under investigation. ...
    Figure 4: Treatments for sarcopenia. It is currently recommended that patients at risk of or suffering from sarcopenia consume a diet high in protein, engage in resistance exercise, and take supplements of the leucine metabolite HMB.     
  21. ^ Landi F, Calvani R, Tosato M, Martone AM, Ortolani E, Savera G, D'Angelo E, Sisto A, Marzetti E (May 2016). "Protein Intake and Muscle Health in Old Age: From Biological Plausibility to Clinical Evidence". Nutrients. 8 (5): 295. doi:10.3390/nu8050295. PMC 4882708  . PMID 27187465. HMB is an active leucine metabolite which activates the mTOR signaling pathway in muscle. Following its absorption, dietary leucine is converted into α-ketoisocaproate (KIC), which is further metabolized into either isovaleryl-CoA or HMB. Under normal conditions, the majority of KIC is converted into isovaleryl-CoA, while only approximately 5% of leucine is metabolized to HMB. This implies that, in order to reach pharmacological levels of HMB, this compound needs to be administered directly, rather than via increasing leucine dosage. ... HMB exerts its effects through protective, anticatabolic mechanisms and directly influences protein synthesis. HMB has also been shown to stabilize the muscle cell membrane, to modulate protein degradation and to up-regulate protein synthesis [68]. 
  22. ^ "Abbott Nutrition Overview" (PDF). Abbott. Abbott Laboratories. Diarsipkan dari versi asli (PDF) tanggal 3 September 2016. Diakses tanggal 3 September 2016. 
  23. ^ Wilson GJ, Wilson JM, Manninen AH (Januari 2008). "Effects of beta-hydroxy-beta-methylbutyrate (HMB) on exercise performance and body composition across varying levels of age, sex, and training experience: A review". Nutrition & Metabolism. 5: 1. doi:10.1186/1743-7075-5-1. PMC 2245953  . PMID 18173841. 
  24. ^ Szcześniak KA, Ostaszewski P, Fuller JC, Ciecierska A, Sadkowski T (June 2015). "Dietary supplementation of β-hydroxy-β-methylbutyrate in animals – a review". Journal of Animal Physiology and Animal Nutrition. 99 (3): 405–417. doi:10.1111/jpn.12234. PMID 25099672. Cholesterol is a major component of the cell membrane, and sarcolemma is the one that relies mainly on de novo synthesis of cholesterol. This is important under stressful conditions when muscle cells may lack the capacity to produce adequate amounts of the cholesterol that is essential to proper functioning of cell membranes. Many biochemical studies have shown that HMB may be a precursor of cholesterol synthesis (Bachhawat et al., 1955; Bloch et al., 1954; Coon et al., 1955; Adamson and Greenberg, 1955; Gey et al., 1957). According to pertinent literature, HMB carbon is incorporated into cholesterol. Therefore, increased intramuscular HMB concentrations may provide readily available substrate for the cholesterol synthesis that is needed to form and stabilize the sarcolemma. ... It is known that HMB supplementation decreases post-exercise levels of enzymes, indicating muscle damage, such as creatinine phosphokinase (CK) and lactate dehydrogenase (LDH), which suggests an enhancement of the muscle cell membrane function. This was shown in numerous studies in humans undergoing both resistance and endurance training (Wilson et al., 2013) ... In theory, HMB use as a precursor to cholesterol could aid in stabilizing muscle cell membranes; however, this has not been confirmed by research studies. The effect of HMB on protein metabolism may in fact help stabilize muscle structure more than any effect HMB may have on cholesterol metabolism in the cell. 
  25. ^ a b Luckose F, Pandey MC, Radhakrishna K (2015). "Effects of amino acid derivatives on physical, mental, and physiological activities". Critical Reviews in Food Science and Nutrition. 55 (13): 1793–1807. doi:10.1080/10408398.2012.708368. PMID 24279396. HMB, a derivative of leucine, prevents muscle damage and increases muscle strength by reducing exercise-induced proteolysis in muscles and also helps in increasing lean body mass. ... HMB is converted to HMB-CoA which is then used for the synthesis of cholesterol in muscle cells (Nissen and Abumrad, 1997). Cholesterol is needed for the growth, repair, and stabilization of cellular membranes during exercise (Chen, 1984). ... The meta analysis studies and the individual studies conducted support the use of HMB as an effective aid to increase body strength, body composition, and to prevent muscle damage during resistance training. 
  26. ^ a b Rahimi MH, Mohammadi H, Eshaghi H, Askari G, Miraghajani M (2018). "The Effects of Beta-Hydroxy-Beta-Methylbutyrate Supplementation on Recovery Following Exercise-Induced Muscle Damage: A Systematic Review and Meta-Analysis". Journal of the American College of Nutrition. 37 (7): 640–649. doi:10.1080/07315724.2018.1451789. PMID 29676656. The current evidence revealed a time-dependent effect of HMB in reducing LDH and CK serum levels among adults. HMB, therefore, may be seen as a priority muscle damage recovery agent in interventions. 
  27. ^ a b c d e Kohlmeier M (May 2015). "Leucine". Nutrient Metabolism: Structures, Functions, and Genes (edisi ke-2nd). Academic Press. hlm. 385–388. ISBN 978-0-12-387784-0. Diarsipkan dari versi asli tanggal 22 March 2018. Diakses tanggal 6 June 2016. Energy fuel: Eventually, most Leu is broken down, providing about 6.0kcal/g. About 60% of ingested Leu is oxidized within a few hours ... Ketogenesis: A significant proportion (40% of an ingested dose) is converted into acetyl-CoA and thereby contributes to the synthesis of ketones, steroids, fatty acids, and other compounds 
    Figure 8.57: Metabolism of L-leucine Diarsipkan 22 March 2018 di Wayback Machine.
  28. ^ "KEGG Reaction: R10759". Kyoto Encyclopedia of Genes and Genomes. Kanehisa Laboratories. Diarsipkan dari versi asli tanggal 1 July 2016. Diakses tanggal 24 June 2016. 
  29. ^ a b Mock DM, Stratton SL, Horvath TD, Bogusiewicz A, Matthews NI, Henrich CL, Dawson AM, Spencer HJ, Owen SN, Boysen G, Moran JH (November 2011). "Urinary excretion of 3-hydroxyisovaleric acid and 3-hydroxyisovaleryl carnitine increases in response to a leucine challenge in marginally biotin-deficient humans". primary source. The Journal of Nutrition. 141 (11): 1925–1930. doi:10.3945/jn.111.146126. PMC 3192457  . PMID 21918059. Reduced activity of MCC impairs catalysis of an essential step in the mitochondrial catabolism of the BCAA leucine. Metabolic impairment diverts methylcrotonyl CoA to 3-hydroxyisovaleryl CoA in a reaction catalyzed by enoyl-CoA hydratase (22, 23). 3-Hydroxyisovaleryl CoA accumulation can inhibit cellular respiration either directly or via effects on the ratios of acyl CoA:free CoA if further metabolism and detoxification of 3-hydroxyisovaleryl CoA does not occur (22). The transfer to carnitine by 4 carnitine acyl-CoA transferases distributed in subcellular compartments likely serves as an important reservoir for acyl moieties (39–41). 3-Hydroxyisovaleryl CoA is likely detoxified by carnitine acetyltransferase producing 3HIA-carnitine, which is transported across the inner mitochondrial membrane (and hence effectively out of the mitochondria) via carnitine-acylcarnitine translocase (39). 3HIA-carnitine is thought to be either directly deacylated by a hydrolase to 3HIA or to undergo a second CoA exchange to again form 3-hydroxyisovaleryl CoA followed by release of 3HIA and free CoA by a thioesterase. 
  30. ^ "KEGG Reaction: R04137". Kyoto Encyclopedia of Genes and Genomes. Kanehisa Laboratories. Diarsipkan dari versi asli tanggal 1 July 2016. Diakses tanggal 24 June 2016. 
  31. ^ "Homo sapiens: 4-hydroxyphenylpyruvate dioxygenase reaction". MetaCyc. SRI International. 20 August 2012. Diakses tanggal 6 June 2016. 
  32. ^ a b c d "3-Hydroxyisovaleric acid". HMDB Version 4.0. Human Metabolome Database. 7 December 2017. Diarsipkan dari versi asli tanggal 5 December 2017. Diakses tanggal 26 December 2017. 
  33. ^ "3-hydroxyisovalerate". Chemical Entities of Biological Interest. European Bioinformatics Institute. 16 September 2014. Diarsipkan dari versi asli tanggal 1 Desember 2017. Diakses tanggal 20 Agustus 2016. 
  34. ^ WO application 2015094925, White TO, "Stable liquid filled hard capsule comprising beta-hydroxy-beta-methylbutyric acid", diterbitkan tanggal 25 Juni 2015, diberikan kepada Capsugel Belgium Nv 
  35. ^ "Beta-Hydroxyisovaleric acid". ChemicalBook. Diarsipkan dari versi asli tanggal 21 Agustus 2016. Diakses tanggal 20 Agustus 2016. 
  36. ^ a b "3-hydroxyisovaleric acid". Chemical Entities of Biological Interest. European Bioinformatics Institute. 23 Oktober 2015. Diarsipkan dari versi asli tanggal 12 Maret 2016. Diakses tanggal 20 Agustus 2016. 
  37. ^ Sitiran pertama bagi sintesis asam β-hidroksi β-metilbutirat dalam basis data kimia Reaxys sejak September 2016 adalah:
    Saytzeff M, Saytzeff A (1877). "Synthese des Allyldimethylcarbinols" [Synthesis of allyldimethylcarbinols]. Justus Liebig's Annalen der Chemie (dalam bahasa Jerman). 185 (2–3): 151–169. doi:10.1002/jlac.18771850204. 
  38. ^ Schirokoff A (January 1881). "Ueber die β-Dipropyl- und β-Diäthyläthylenmilchsäure und über die Oxydation des Allyldimethylcarbinols und Diallylcarbinols mit übermangansaurem Kalium" [On the β-dipropyl- and β-diethylenyl-lactic acid, and on the oxidation of the allyl dimethylcarbinol and diallylcarbinol with excess potassium]. Journal für Praktische Chemie (dalam bahasa Jerman). 23 (1): 196–208. doi:10.1002/prac.18810230115. 
  39. ^ Reformatzky B (30 October 1889). "Synthese einiger Glycerine mittelst unterchloriger Säure" [Synthesis of some glycerol by hypochlorous acid]. Journal für Praktische Chemie (dalam bahasa Jerman). 40 (1): 396–419. doi:10.1002/prac.18890400137. 
  40. ^ McMurry, John E. (2010). "Oxidation of Alkenes: Epoxidation, Hydroxylation, and Cleavage". Fundamentals of Organic Chemistry (edisi ke-7th). Cengage Learning. hlm. 124–126, 142. ISBN 9781439049716. 
  41. ^ Kondakow J (1892). "On the action of mineral acids on dimethylallyls". Zhurnal Russkago Fiziko-Khimicheskago Obshchestva (Journal of the Russian Physico-Chemical Society) (dalam bahasa Russian). 1: 508–513.  abstrak oleh Grosset (1893). "Ueber die Einwirkung von Mineralsauren auk Dimethylallen" [On the action of mineral acids on dimethylallyls]. Berichte der Deutschen Chemischen Gesellschaft (dalam bahasa German). 26 (4): 96. doi:10.1002/cber.18930260412. 
  42. ^ Gresham TL, Jansen JE, Shaver FW, Beears WL (January 1954). "β-Propiolactone. XIV. β-Isovalerolactone". Journal of the American Chemical Society. 76 (2): 486–488. doi:10.1021/ja01631a045. 
  43. ^ WO application 2012140276, Noti C, Schmid L, Rittiner B, Hanselmann P, Bierstedt A, "Process for the preparation of 3-hydroxy-3-methylbutyric acid or its calcium salts", diterbitkan tanggal 10 January 2013, diberikan kepada Lonza Ltd 
  44. ^ Kohn M (September 1903). "Zur Kenntnis des Diacetonalkohols und des Mesityloxyds" [Knowledge of diacetone alkohols and mesityl oxide]. Monatshefte für Chemie und Verwandte Teile Anderer Wissenschaften. 24 (9): 765–772. doi:10.1007/BF01526057. 
  45. ^ Doraiswamy LK (February 2001). "Example 5.2". Organic Synthesis Engineering. New York: Oxford University Press. hlm. 102–124. ISBN 978-0-19-509689-7. 

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