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Pyruvate dehydrogenase kinase

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Pyruvate dehydrogenase kinase

Pyruvate dehydrogenase kinase (also pyruvate dehydrogenase complex kinase, PDC kinase, or PDK; EC 2.7.11.2) is a kinase enzyme which acts to inactivate the enzyme pyruvate dehydrogenase by phosphorylating it using ATP.

PDK thus participates in the regulation of the pyruvate dehydrogenase complex of which pyruvate dehydrogenase is the first component. Both PDK and the pyruvate dehydrogenase complex are located in the mitochondrial matrix of eukaryotes. The complex acts to convert pyruvate (a product of glycolysis in the cytosol) to acetyl-coA, which is then oxidized in the mitochondria to produce energy, in the citric acid cycle. By downregulating the activity of this complex, PDK will decrease the oxidation of pyruvate in mitochondria and increase the conversion of pyruvate to lactate in the cytosol.

The opposite action of PDK, namely the dephosphorylation and activation of pyruvate dehydrogenase, is catalyzed by a phosphoprotein phosphatase called pyruvate dehydrogenase phosphatase.

(Pyruvate dehydrogenase kinase should not be confused with Phosphoinositide-dependent kinase-1, which is also sometimes known as "PDK1".)

Contents

  • Phosphorylation Sites 1
  • Isozymes 2
  • Mechanism 3
  • Regulation 4
  • Disease Relevance 5
  • References 6
  • External links 7

Phosphorylation Sites

The areas around the three phosphorylation sites are shown in red. Site 1 is in the bottom left corner, site 2 in the top right, and site 3 in the bottom right.

PDK can phosphorylate a serine residue on pyruvate dehydrogenase at three possible sites. Some evidence has shown that phosphorylation at site 1 will nearly completely deactivate the enzyme while phosphorylation at sites 2 and 3 had only a small contribution to complex inactivation.[1] Therefore, it is phosphorylation at site 1 that is responsible for pyruvate dehydrogenase deactivation.

Isozymes

There are four known isozymes of PDK in humans:

The primary sequencing between the four isozymes are conserved with 70% identity. The greatest differences occur near the N-terminus.[2]

PDK1 is the largest of the four with 436 residues while PDK2, PDK3 and PDK4 have 407, 406, and 411 residues respectively. The isozymes have different activity and phosphorylation rates at each site. At site 1 in order from fastest to slowest, PDK2 > PDK4 ≈ PDK1 > PDK3. For site 2, PDK3 > PDK4 > PDK2 > PDK1. Only PDK1 can phosphorylate site 3. However, it has been shown that these activities are sensitive to slight changes in pH so the microenvironment of the PDK isozymes may change the reaction rates.[3][4]

Isozyme abundance has also been shown to be tissue specific. PDK1 is ample in heart cells. PDK3 is most abundant in testis. PDK2 is present in most tissues but low in spleen and lung cells. PDK4 is predominantly found in skeletal muscle and heart tissues.[5]

Mechanism

Pyruvate dehydrogenase is deactivated when phosphorylated by PDK. Normally, the active site of pyruvate dehydrogenase is in a stabilized and ordered conformation supported by a network of hydrogen bonds. However, phosphorylation by PDK at site 1 causes steric clashes with another nearby serine residue due to both the increased size and negative charges associated with the phosphorylated residue.[6] This disrupts the hydrogen bond network and disorders the conformation of two phosphorylation loops. These loops prevent the reductive acetylation step, thus halting overall activity of the enzyme.[7] The conformational changes and mechanism of deactivation for phosphorylation at sites 2 and 3 are not known at this time.

Regulation

PDK isozyme 4 with ADP bound in the active site. ADP has been shown to be a competitive inhibitor.[8]

Pyruvate dehydrogenase kinase is activated by ATP, NADH and acetyl-CoA. It is inhibited by ADP, NAD+, CoA-SH and pyruvate.[9]

Each isozyme responds to each of these factors slightly differently. NADH stimulates PDK1 activity by 20% and PDK2 activity by 30%. NADH with acetyl-CoA increases activity in these enzymes by 200% and 300% respectively. In similar conditions, PDK3 is unresponsive to NADH and inhibited by NADH with acetyl-CoA. PDK4 has a 200% activity increase with NADH, but adding acetyl-CoA does not increase activity further.[5]

Disease Relevance

Some studies have shown that cells that lack insulin (or are insensitive to insulin) overexpress PDK4.[10] As a result, the pyruvate formed from glycolysis cannot be oxidized which leads to hyperglycaemia due to the fact that glucose in the blood cannot be used efficiently. Therefore, several drugs target PDK4 hoping to treat type II diabetes.[11]

PDK1 has shown to have increased activity in hypoxic cancer cells due to the presence of HIF-1. PDK1 shunts pyruvate away from the citric acid cycle and keeps the hypoxic cell alive.[12] Therefore, PDK1 inhibition has been suggested as an antitumor therapy since PDK1 prevents apoptosis in these cancerous cells.[13] Similarly, PDK3 has been shown to be overexpressed in colon cancer cell lines.[14] Three proposed inhibitors are AZD7545 and dichloroacetate which both bind to PDK1, and Radicicol which binds to PDK3.[15]

References


-- Module:Hatnote -- -- -- -- This module produces hatnote links and links to related articles. It -- -- implements the and meta-templates and includes -- -- helper functions for other Lua hatnote modules. --


local libraryUtil = require('libraryUtil') local checkType = libraryUtil.checkType local mArguments -- lazily initialise Module:Arguments local yesno -- lazily initialise Module:Yesno

local p = {}


-- Helper functions


local function getArgs(frame) -- Fetches the arguments from the parent frame. Whitespace is trimmed and -- blanks are removed. mArguments = require('Module:Arguments') return mArguments.getArgs(frame, {parentOnly = true}) end

local function removeInitialColon(s) -- Removes the initial colon from a string, if present. return s:match('^:?(.*)') end

function p.findNamespaceId(link, removeColon) -- Finds the namespace id (namespace number) of a link or a pagename. This -- function will not work if the link is enclosed in double brackets. Colons -- are trimmed from the start of the link by default. To skip colon -- trimming, set the removeColon parameter to true. checkType('findNamespaceId', 1, link, 'string') checkType('findNamespaceId', 2, removeColon, 'boolean', true) if removeColon ~= false then link = removeInitialColon(link) end local namespace = link:match('^(.-):') if namespace then local nsTable = mw.site.namespaces[namespace] if nsTable then return nsTable.id end end return 0 end

function p.formatPages(...) -- Formats a list of pages using formatLink and returns it as an array. Nil -- values are not allowed. local pages = {...} local ret = {} for i, page in ipairs(pages) do ret[i] = p._formatLink(page) end return ret end

function p.formatPageTables(...) -- Takes a list of page/display tables and returns it as a list of -- formatted links. Nil values are not allowed. local pages = {...} local links = {} for i, t in ipairs(pages) do checkType('formatPageTables', i, t, 'table') local link = t[1] local display = t[2] links[i] = p._formatLink(link, display) end return links end

function p.makeWikitextError(msg, helpLink, addTrackingCategory) -- Formats an error message to be returned to wikitext. If -- addTrackingCategory is not false after being returned from -- Module:Yesno, and if we are not on a talk page, a tracking category -- is added. checkType('makeWikitextError', 1, msg, 'string') checkType('makeWikitextError', 2, helpLink, 'string', true) yesno = require('Module:Yesno') local title = mw.title.getCurrentTitle() -- Make the help link text. local helpText if helpLink then helpText = ' (help)' else helpText = end -- Make the category text. local category if not title.isTalkPage and yesno(addTrackingCategory) ~= false then category = 'Hatnote templates with errors' category = string.format( '%s:%s', mw.site.namespaces[14].name, category ) else category = end return string.format( '%s', msg, helpText, category ) end


-- Format link -- -- Makes a wikilink from the given link and display values. Links are escaped -- with colons if necessary, and links to sections are detected and displayed -- with " § " as a separator rather than the standard MediaWiki "#". Used in -- the template.


function p.formatLink(frame) local args = getArgs(frame) local link = args[1] local display = args[2] if not link then return p.makeWikitextError( 'no link specified', 'Template:Format hatnote link#Errors', args.category ) end return p._formatLink(link, display) end

function p._formatLink(link, display) -- Find whether we need to use the colon trick or not. We need to use the -- colon trick for categories and files, as otherwise category links -- categorise the page and file links display the file. checkType('_formatLink', 1, link, 'string') checkType('_formatLink', 2, display, 'string', true) link = removeInitialColon(link) local namespace = p.findNamespaceId(link, false) local colon if namespace == 6 or namespace == 14 then colon = ':' else colon = end -- Find whether a faux display value has been added with the | magic -- word. if not display then local prePipe, postPipe = link:match('^(.-)|(.*)$') link = prePipe or link display = postPipe end -- Find the display value. if not display then local page, section = link:match('^(.-)#(.*)$') if page then display = page .. ' § ' .. section end end -- Assemble the link. if display then return string.format('%s', colon, link, display) else return string.format('%s%s', colon, link) end end


-- Hatnote -- -- Produces standard hatnote text. Implements the template.


function p.hatnote(frame) local args = getArgs(frame) local s = args[1] local options = {} if not s then return p.makeWikitextError( 'no text specified', 'Template:Hatnote#Errors', args.category ) end options.extraclasses = args.extraclasses options.selfref = args.selfref return p._hatnote(s, options) end

function p._hatnote(s, options) checkType('_hatnote', 1, s, 'string') checkType('_hatnote', 2, options, 'table', true) local classes = {'hatnote'} local extraclasses = options.extraclasses local selfref = options.selfref if type(extraclasses) == 'string' then classes[#classes + 1] = extraclasses end if selfref then classes[#classes + 1] = 'selfref' end return string.format( '
%s
', table.concat(classes, ' '), s )

end

return p-------------------------------------------------------------------------------- -- Module:Hatnote -- -- -- -- This module produces hatnote links and links to related articles. It -- -- implements the and meta-templates and includes -- -- helper functions for other Lua hatnote modules. --


local libraryUtil = require('libraryUtil') local checkType = libraryUtil.checkType local mArguments -- lazily initialise Module:Arguments local yesno -- lazily initialise Module:Yesno

local p = {}


-- Helper functions


local function getArgs(frame) -- Fetches the arguments from the parent frame. Whitespace is trimmed and -- blanks are removed. mArguments = require('Module:Arguments') return mArguments.getArgs(frame, {parentOnly = true}) end

local function removeInitialColon(s) -- Removes the initial colon from a string, if present. return s:match('^:?(.*)') end

function p.findNamespaceId(link, removeColon) -- Finds the namespace id (namespace number) of a link or a pagename. This -- function will not work if the link is enclosed in double brackets. Colons -- are trimmed from the start of the link by default. To skip colon -- trimming, set the removeColon parameter to true. checkType('findNamespaceId', 1, link, 'string') checkType('findNamespaceId', 2, removeColon, 'boolean', true) if removeColon ~= false then link = removeInitialColon(link) end local namespace = link:match('^(.-):') if namespace then local nsTable = mw.site.namespaces[namespace] if nsTable then return nsTable.id end end return 0 end

function p.formatPages(...) -- Formats a list of pages using formatLink and returns it as an array. Nil -- values are not allowed. local pages = {...} local ret = {} for i, page in ipairs(pages) do ret[i] = p._formatLink(page) end return ret end

function p.formatPageTables(...) -- Takes a list of page/display tables and returns it as a list of -- formatted links. Nil values are not allowed. local pages = {...} local links = {} for i, t in ipairs(pages) do checkType('formatPageTables', i, t, 'table') local link = t[1] local display = t[2] links[i] = p._formatLink(link, display) end return links end

function p.makeWikitextError(msg, helpLink, addTrackingCategory) -- Formats an error message to be returned to wikitext. If -- addTrackingCategory is not false after being returned from -- Module:Yesno, and if we are not on a talk page, a tracking category -- is added. checkType('makeWikitextError', 1, msg, 'string') checkType('makeWikitextError', 2, helpLink, 'string', true) yesno = require('Module:Yesno') local title = mw.title.getCurrentTitle() -- Make the help link text. local helpText if helpLink then helpText = ' (help)' else helpText = end -- Make the category text. local category if not title.isTalkPage and yesno(addTrackingCategory) ~= false then category = 'Hatnote templates with errors' category = string.format( '%s:%s', mw.site.namespaces[14].name, category ) else category = end return string.format( '%s', msg, helpText, category ) end


-- Format link -- -- Makes a wikilink from the given link and display values. Links are escaped -- with colons if necessary, and links to sections are detected and displayed -- with " § " as a separator rather than the standard MediaWiki "#". Used in -- the template.


function p.formatLink(frame) local args = getArgs(frame) local link = args[1] local display = args[2] if not link then return p.makeWikitextError( 'no link specified', 'Template:Format hatnote link#Errors', args.category ) end return p._formatLink(link, display) end

function p._formatLink(link, display) -- Find whether we need to use the colon trick or not. We need to use the -- colon trick for categories and files, as otherwise category links -- categorise the page and file links display the file. checkType('_formatLink', 1, link, 'string') checkType('_formatLink', 2, display, 'string', true) link = removeInitialColon(link) local namespace = p.findNamespaceId(link, false) local colon if namespace == 6 or namespace == 14 then colon = ':' else colon = end -- Find whether a faux display value has been added with the | magic -- word. if not display then local prePipe, postPipe = link:match('^(.-)|(.*)$') link = prePipe or link display = postPipe end -- Find the display value. if not display then local page, section = link:match('^(.-)#(.*)$') if page then display = page .. ' § ' .. section end end -- Assemble the link. if display then return string.format('%s', colon, link, display) else return string.format('%s%s', colon, link) end end


-- Hatnote -- -- Produces standard hatnote text. Implements the template.


function p.hatnote(frame) local args = getArgs(frame) local s = args[1] local options = {} if not s then return p.makeWikitextError( 'no text specified', 'Template:Hatnote#Errors', args.category ) end options.extraclasses = args.extraclasses options.selfref = args.selfref return p._hatnote(s, options) end

function p._hatnote(s, options) checkType('_hatnote', 1, s, 'string') checkType('_hatnote', 2, options, 'table', true) local classes = {'hatnote'} local extraclasses = options.extraclasses local selfref = options.selfref if type(extraclasses) == 'string' then classes[#classes + 1] = extraclasses end if selfref then classes[#classes + 1] = 'selfref' end return string.format( '
%s
', table.concat(classes, ' '), s )

end

return p
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External links

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