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Homocysteine
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<h2 id="biosynthesis-and-biochemical-roles">Biosynthesis and biochemical roles</h2> <p>Homocysteine is biosynthesized naturally via a multi-step process.<a class="footnote-ref" id="fnref:7" href="#fn:7"><sup>7</sup></a> First, methionine receives an adenosine group from <a href="/facts/Adenosine_triphosphate/nB9bwgcU">ATP</a>, a reaction catalyzed by <a href="/facts/S-adenosyl-methionine_synthetase/brKs4maf">S-adenosyl-methionine synthetase</a>, to give <a href="/facts/S-adenosyl_methionine/oAsJ0SSR"><i>S</i>-adenosyl methionine</a> (SAM). SAM is widely used source of methyl radicals as a cofactor for <a href="/facts/Radical_SAM_enzymes/obEgmg5f">radical SAM enzymes</a>. Transfer of the methyl group to an acceptor molecule gives S-adenosyl-homocysteine. <a href="/facts/Hydrolysis/JTvwIHPs">Hydrolysis</a> of this thioether gives L-homocysteine. L-Homocysteine reacts with <a href="/facts/Tetrahydrofolate/6yEeP8JS">tetrahydrofolate</a> (THF) to give <a href="/facts/Methionine/7neydPKo">L-methionine</a>.<a class="footnote-ref" id="fnref:8" href="#fn:8"><sup>8</sup></a> </p> <h3>Biosynthesis of cysteine</h3> <p>Mammals biosynthesize the amino acid cysteine via homocysteine. <a href="/facts/Cystathionine-beta-synthase/E3SMBtvP">Cystathionine β-synthase</a> catalyses the condensation of homocysteine and <a href="/facts/Serine/4duVl30B">serine</a> to give <a href="/facts/Cystathionine/n4ytaqjj">cystathionine</a>. This reaction uses <a href="/facts/Pyridoxine/sRTLFpv1">pyridoxine</a> (vitamin B6) as a cofactor. <a href="/facts/Cystathionine_gamma-lyase/eS2hxSza">Cystathionine γ-lyase</a> then converts this double amino acid to cysteine, ammonia, and α-ketobutyrate. Bacteria and plants rely on a different pathway to produce cysteine, relying on <i>O</i>-acetylserine.<a class="footnote-ref" id="fnref:9" href="#fn:9"><sup>9</sup></a> </p> <h3>Methionine salvage</h3> <p>Homocysteine can be recycled into <a href="/facts/Methionine/7neydPKo">methionine</a>. This process uses N5-methyl tetrahydrofolate as the methyl donor and <a href="/facts/Cobalamin/vCk613gD">cobalamin</a> (vitamin B12)-related enzymes. More detail on these enzymes can be found in the article for <a href="/facts/Methionine_synthase/NpTvMn2T">methionine synthase</a>. </p> <h3>Other reactions of biochemical significance</h3> <p>Homocysteine can cyclize to give <a href="/facts/Homocysteine_thiolactone/wQ9UspnG">homocysteine thiolactone</a>, a five-membered <a href="/facts/Heterocycle/8oYSjJxY">heterocycle</a>. Because of this "self-looping" reaction, homocysteine-containing <a href="/facts/Peptide/C4ltc7UG">peptides</a> tend to cleave themselves by reactions generating <a href="/facts/Oxidative_stress/HX7dfUUb">oxidative stress</a>.<a class="footnote-ref" id="fnref:10" href="#fn:10"><sup>10</sup></a> </p><p>Homocysteine also acts as an <a href="/facts/Allosteric_modulator/Gg1It5Cj">allosteric antagonist</a> at Dopamine D2 receptors.<a class="footnote-ref" id="fnref:11" href="#fn:11"><sup>11</sup></a> </p><p>It has been proposed that both homocysteine and its thiolactone may have played a significant role in the <a href="/facts/Abiogenesis/BvAmLPQP">appearance of life</a> on the early Earth.<a class="footnote-ref" id="fnref:12" href="#fn:12"><sup>12</sup></a> </p> <h2 id="homocysteine-levels">Homocysteine levels</h2> <p>Homocysteine levels typically are higher in men than women, and increase with age.<a class="footnote-ref" id="fnref:13" href="#fn:13"><sup>13</sup></a><a class="footnote-ref" id="fnref:14" href="#fn:14"><sup>14</sup></a> </p><p>Common levels in Western populations are 10 to 12 μmol/L, and levels of 20 μmol/L are found in populations with low B-vitamin intakes or in the elderly (e.g., Rotterdam, Framingham).<a class="footnote-ref" id="fnref:15" href="#fn:15"><sup>15</sup></a><a class="footnote-ref" id="fnref:16" href="#fn:16"><sup>16</sup></a> </p><p>It is decreased with methyl folate trapping, where it is accompanied by decreased methylmalonic acid, increased folate, and a decrease in <a href="/facts/Formiminoglutamic_acid/pFH6RPPm">formiminoglutamic acid</a>.<a class="footnote-ref" id="fnref:17" href="#fn:17"><sup>17</sup></a> This is the opposite of MTHFR C677T mutations, which result in an increase in homocysteine. </p> <a href="/facts/Reference_ranges_for_blood_tests/Fls5Gbtb">Blood reference ranges</a> for homocysteine:<table><tbody><tr><td>Sex</td><td>Age</td><td>Lower limit</td><td>Upper limit</td><td>Unit</td><td>Elevated</td><td><a href="/facts/Optimal_health_range/IqNt7ELQ">Therapeutic target</a></td></tr><tr><td rowspan="4">Female</td><td rowspan="2">12–19 years</td><td>3.3<a class="footnote-ref" id="fnref:18" href="#fn:18"><sup>18</sup></a></td><td>7.2<a class="footnote-ref" id="fnref:19" href="#fn:19"><sup>19</sup></a></td><td>μmol/L</td><td rowspan="4">> 10.4 μmol/L or > 140 μg/dl</td><td rowspan="8">< 6.3 μmol/L<a class="footnote-ref" id="fnref:20" href="#fn:20"><sup>20</sup></a> or < 85 μg/dL<a class="footnote-ref" id="fnref:21" href="#fn:21"><sup>21</sup></a></td></tr><tr><td>45<a class="footnote-ref" id="fnref:22" href="#fn:22"><sup>22</sup></a></td><td>100<a class="footnote-ref" id="fnref:23" href="#fn:23"><sup>23</sup></a></td><td>μg/dL</td></tr><tr><td rowspan="2">>60 years</td><td>4.9<a class="footnote-ref" id="fnref:24" href="#fn:24"><sup>24</sup></a></td><td>11.6<a class="footnote-ref" id="fnref:25" href="#fn:25"><sup>25</sup></a></td><td>μmol/L</td></tr><tr><td>66<a class="footnote-ref" id="fnref:26" href="#fn:26"><sup>26</sup></a></td><td>160<a class="footnote-ref" id="fnref:27" href="#fn:27"><sup>27</sup></a></td><td>μg/dL</td></tr><tr><td rowspan="4">Male</td><td rowspan="2">12–19 years</td><td>4.3<a class="footnote-ref" id="fnref:28" href="#fn:28"><sup>28</sup></a></td><td>9.9<a class="footnote-ref" id="fnref:29" href="#fn:29"><sup>29</sup></a></td><td>μmol/L</td><td rowspan="4">> 11.4 μmol/L or > 150 μg/dL</td></tr><tr><td>60<a class="footnote-ref" id="fnref:30" href="#fn:30"><sup>30</sup></a></td><td>130<a class="footnote-ref" id="fnref:31" href="#fn:31"><sup>31</sup></a></td><td>μg/dL</td></tr><tr><td rowspan="2">>60 years</td><td>5.9<a class="footnote-ref" id="fnref:32" href="#fn:32"><sup>32</sup></a></td><td>15.3<a class="footnote-ref" id="fnref:33" href="#fn:33"><sup>33</sup></a></td><td>μmol/L</td></tr><tr><td>80<a class="footnote-ref" id="fnref:34" href="#fn:34"><sup>34</sup></a></td><td>210<a class="footnote-ref" id="fnref:35" href="#fn:35"><sup>35</sup></a></td><td>μg/dL</td></tr></tbody></table> <p>The ranges above are provided as examples only; test results always should be interpreted using the range provided by the laboratory that produced the result. </p> <h2 id="elevated-homocysteine">Elevated homocysteine</h2> <p class="note">Main article: <a href="/facts/Hyperhomocysteinemia/PIosnq0g">Hyperhomocysteinemia</a></p> <p>Abnormally high levels of homocysteine in the serum, above 15 μmol/L, are a medical condition called <a href="/facts/Hyperhomocysteinemia/PIosnq0g">hyperhomocysteinemia</a>.<a class="footnote-ref" id="fnref:36" href="#fn:36"><sup>36</sup></a> This has been claimed to be a significant risk factor for the development of a wide range of diseases, in total more than 100<a class="footnote-ref" id="fnref:37" href="#fn:37"><sup>37</sup></a> including <a href="/facts/Thrombosis/8Y3wh2UX">thrombosis</a>,<a class="footnote-ref" id="fnref:38" href="#fn:38"><sup>38</sup></a> neuropsychiatric illness,<a class="footnote-ref" id="fnref:39" href="#fn:39"><sup>39</sup></a><a class="footnote-ref" id="fnref:40" href="#fn:40"><sup>40</sup></a><a class="footnote-ref" id="fnref:41" href="#fn:41"><sup>41</sup></a><a class="footnote-ref" id="fnref:42" href="#fn:42"><sup>42</sup></a> in particular dementia<a class="footnote-ref" id="fnref:43" href="#fn:43"><sup>43</sup></a> and fractures.<a class="footnote-ref" id="fnref:44" href="#fn:44"><sup>44</sup></a><a class="footnote-ref" id="fnref:45" href="#fn:45"><sup>45</sup></a> It also is found to be associated with microalbuminuria (<a href="/facts/Microalbuminuria/9BNNAEWd">moderately increased albuminuria</a>), which is a strong indicator of the risk of future cardiovascular disease and renal dysfunction.<a class="footnote-ref" id="fnref:46" href="#fn:46"><sup>46</sup></a> Vitamin B12 deficiency, even when coupled with high serum folate levels, has been found to increase overall homocysteine concentrations as well.<a class="footnote-ref" id="fnref:47" href="#fn:47"><sup>47</sup></a> </p><p>Typically, hyperhomocysteinemia is managed with vitamin B6, vitamin B9, and vitamin B12 supplementation.<a class="footnote-ref" id="fnref:48" href="#fn:48"><sup>48</sup></a> However, supplementation with these vitamins does not appear to improve cardiovascular disease outcomes.<a class="footnote-ref" id="fnref:49" href="#fn:49"><sup>49</sup></a> </p> <h2 id="external-links">External links</h2> Wikiversity has learning resources about <i>Homocysteine</i> <ul><li><a href="http://gmd.mpimp-golm.mpg.de/Spectrums/2115c92f-87df-468a-a708-c16705b68729.aspx">Homocysteine MS Spectrum</a></li> <li>Homocysteine at <a href="https://www.testing.com/tests/homocysteine/">Lab Tests Online</a></li> <li><a href="http://www.abc.net.au/rn/healthreport/stories/2010/2905728.htm">Prof. David Spence on homocysteine levels, kidney damage, and cardiovascular disease</a>, <i>The Health Report</i>, Radio National, 24 May 2010</li></ul> <h2 id="references">References</h2> <ol> <li id="fn:1"><p>"Homocysteine" (PDF). moh.gov.vn. Retrieved 5 April 2023. <a href="https://dmec.moh.gov.vn/documents/10182/31934092/upload_00034511_1656320270953.pdf?version=1.0&fileId=31960513" target="_blank">https://dmec.moh.gov.vn/documents/10182/31934092/upload_00034511_1656320270953.pdf?version=1.0&fileId=31960513</a> <a href="#fnref:1" class="footnote-back-ref">↩</a></p></li> <li id="fn:2"><p>Kim J, Kim H, Roh H, Kwon Y (2018). "Causes of hyperhomocysteinemia and its pathological significance". Arch Pharm Res. 41 (4): 372–383. doi:10.1007/s12272-018-1016-4. PMID 29552692. S2CID 3986295.{{cite journal}}: CS1 maint: multiple names: authors list (link) <a href="https://pubmed.ncbi.nlm.nih.gov/29552692" target="_blank">https://pubmed.ncbi.nlm.nih.gov/29552692</a> <a href="#fnref:2" class="footnote-back-ref">↩</a></p></li> <li id="fn:3"><p>Boudi, Brian F. "Noncoronary Atherosclerosis". Medscape. 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"THE METHYL FOLATE TRAP: A physiological response in man to prevent methyl group deficiency in kwashiorkor (methionine deficiency) and an explanation for folic-acid-induced exacerbation of subacute combined degeneration in pernicious anaemia". The Lancet. 318 (8242): 337–340. doi:10.1016/S0140-6736(81)90650-4. ISSN 0140-6736. PMID 6115113. S2CID 29977127. <a href="/wiki/Doi_(identifier)" target="_blank">/wiki/Doi_(identifier)</a> <a href="#fnref:17" class="footnote-back-ref">↩</a></p></li> <li id="fn:18"><p>"Homocysteine". www.thedoctorsdoctor.com. Archived from the original on 2008-12-05. Retrieved 2008-11-22. <a href="https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm" target="_blank">https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm</a> <a href="#fnref:18" class="footnote-back-ref">↩</a></p></li> <li id="fn:19"><p>"Homocysteine". www.thedoctorsdoctor.com. Archived from the original on 2008-12-05. Retrieved 2008-11-22. <a href="https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm" target="_blank">https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm</a> <a href="#fnref:19" class="footnote-back-ref">↩</a></p></li> <li id="fn:20"><p>Adëeva Nutritionals Canada > Optimal blood test values Archived 2009-05-29 at the Wayback Machine Retrieved on July 9, 2009 <a href="http://www.adeeva.com/resources/bloodtestscomplete.html" target="_blank">http://www.adeeva.com/resources/bloodtestscomplete.html</a> <a href="#fnref:20" class="footnote-back-ref">↩</a></p></li> <li id="fn:21"><p>Adëeva Nutritionals Canada > Optimal blood test values Archived 2009-05-29 at the Wayback Machine Retrieved on July 9, 2009 <a href="http://www.adeeva.com/resources/bloodtestscomplete.html" target="_blank">http://www.adeeva.com/resources/bloodtestscomplete.html</a> <a href="#fnref:21" class="footnote-back-ref">↩</a></p></li> <li id="fn:22"><p>Derived from molar values using molar massof 135 g/mol <a href="#fnref:22" class="footnote-back-ref">↩</a></p></li> <li id="fn:23"><p>Derived from molar values using molar massof 135 g/mol <a href="#fnref:23" class="footnote-back-ref">↩</a></p></li> <li id="fn:24"><p>"Homocysteine". www.thedoctorsdoctor.com. Archived from the original on 2008-12-05. Retrieved 2008-11-22. <a href="https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm" target="_blank">https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm</a> <a href="#fnref:24" class="footnote-back-ref">↩</a></p></li> <li id="fn:25"><p>"Homocysteine". www.thedoctorsdoctor.com. Archived from the original on 2008-12-05. Retrieved 2008-11-22. <a href="https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm" target="_blank">https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm</a> <a href="#fnref:25" class="footnote-back-ref">↩</a></p></li> <li id="fn:26"><p>Derived from molar values using molar massof 135 g/mol <a href="#fnref:26" class="footnote-back-ref">↩</a></p></li> <li id="fn:27"><p>Derived from molar values using molar massof 135 g/mol <a href="#fnref:27" class="footnote-back-ref">↩</a></p></li> <li id="fn:28"><p>"Homocysteine". www.thedoctorsdoctor.com. Archived from the original on 2008-12-05. Retrieved 2008-11-22. <a href="https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm" target="_blank">https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm</a> <a href="#fnref:28" class="footnote-back-ref">↩</a></p></li> <li id="fn:29"><p>"Homocysteine". www.thedoctorsdoctor.com. Archived from the original on 2008-12-05. Retrieved 2008-11-22. <a href="https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm" target="_blank">https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm</a> <a href="#fnref:29" class="footnote-back-ref">↩</a></p></li> <li id="fn:30"><p>Derived from molar values using molar massof 135 g/mol <a href="#fnref:30" class="footnote-back-ref">↩</a></p></li> <li id="fn:31"><p>Derived from molar values using molar massof 135 g/mol <a href="#fnref:31" class="footnote-back-ref">↩</a></p></li> <li id="fn:32"><p>"Homocysteine". www.thedoctorsdoctor.com. Archived from the original on 2008-12-05. Retrieved 2008-11-22. <a href="https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm" target="_blank">https://web.archive.org/web/20081205050029/http://www.thedoctorsdoctor.com/labtests/homocysteine.htm</a> <a href="#fnref:32" class="footnote-back-ref">↩</a></p></li> <li id="fn:33"><p>"Homocysteine". www.thedoctorsdoctor.com. Archived from the original on 2008-12-05. 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