Branched-chain alpha-keto acid dehydrogenase complex

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Branched chain oxoacid dehydrogenase
)

The branched-chain α-ketoacid dehydrogenase complex (BCKDC or BCKDH complex) is a multi-subunit complex of

Krebs cycle
.

Biological function

In animal tissue, BCKDC catalyzes an irreversible step

hydrocarbons
.

The overall catabolic reaction catalyzed by the BCKDC is shown in Figure 1.

Figure 1: This is the overall reaction catalyzed by the branched-chain alpha-ketoacid dehydrogenase complex.

Structure

The mechanism of enzymatic catalysis by the BCKDC draws largely upon the elaborate structure of this large enzyme complex. This enzyme complex is composed of three catalytic components:

Unit EC number Name Gene Cofactor
E1 EC 1.2.4.4 alpha-ketoacid dehydrogenase BCKDHA thiamine pyrophosphate (TPP)
E2 EC 2.3.1.168 dihydrolipoyl transacylase DBT lipoic acid, coenzyme A
E3 EC 1.8.1.4 dihydrolipoamide dehydrogenase DLD FAD, NAD

In humans, 24 copies of E2 arranged in octahedral symmetry form the core of the BCKDC.

carboxy-terminal portion. The inner-core domain is linked to the other two domains of the E2 subunit by two interdomain segments (linkers).[9] The inner-core domain is necessary to form the oligomeric core of the enzyme complex and catalyzes the acyltransferase reaction (shown in the "Mechanism" section below).[10] The lipoyl domain of E2 is free to swing between the active sites of the E1, E2, and E3 subunits on the assembled BCKDC by virtue of the conformational flexibility of the aforementioned linkers (see Figure 2).[11][12]
Thus, in terms of function as well as structure, the E2 component plays a central role in the overall reaction catalyzed by the BCKDC.

Figure 2:This is a schematic of the "swinging" lipoyl domain. Note that this lipoyl domain is covalently attached to the E2 subunit of the BCKDC, but is free to swing between the E1, E2, and E3 subunits. As is described in the "Mechanism" section, the ability of the lipoyl group to freely swing between the active sites on each of the three subunits of the BCKDC plays a large and important role in the catalytic activity of this enzyme complex.[13]

The role of each subunit is as follows:

E1 subunit

E1 uses thiamine pyrophosphate (TPP) as a catalytic cofactor. E1 catalyzes both the decarboxylation of the α-ketoacid and the subsequent reductive acylation of the lipoyl moiety (another catalytic cofactor) that is covalently bound to E2.

E2 subunit

E2 catalyzes a transfer of the acyl group from the lipoyl moiety to coenzyme A (a stoichiometric cofactor).[14]

E3 subunit

The E3 component is a flavoprotein, and it re-oxidizes the reduced lipoyl sulfur residues of E2 using FAD (a catalytic cofactor) as the oxidant. FAD then transfers these protons and electrons to NAD+ (a stoichiometric cofactor) to complete the reaction cycle.

Mechanism

As previously mentioned, BCKDC's primary function in mammals is to catalyze an irreversible step in the catabolism of branched-chain amino acids. However BCKDC has a relatively broad specificity, also oxidizing 4-methylthio-2-oxobutyrate and 2-oxobutyrate at comparable rates and with similar Km values as for its branched-chain amino acid substrates.[15] The BCKDC will also oxidize pyruvate, but at such a slow rate this side reaction has very little physiological significance.[16][17]

The reaction mechanism is as follows.[18] Please note that any of several branched-chain α-ketoacids could have been used as a starting material; for this example, α-ketoisovalerate was arbitrarily chosen as the BCKDC substrate.

NOTE: Steps 1 and 2 occur in the E1 domain

STEP 1: α-ketoisovalerate combines with TPP and is then decarboxylated. The proper arrow-pushing mechanism is shown in Figure 3.

Figure 3: α-ketoisovalerate combines with TPP and is then decarboxylated

STEP 2: The 2-methylpropanol-TPP is oxidized to form an acyl group while being simultaneously transferred to the lipoyl cofactor on E2. Note that TPP is regenerated. The proper arrow-pushing mechanism is shown in Figure 4.

Figure 4: The 2-methylpropanol-TPP is oxidized to form an acyl group while being simultaneously transferred to the lipoyl cofactor on E2. Note that TPP is regenerated.
NOTE: The acylated lipoyl arm now leaves E1 and swings into the E2 active site, where Step 3 occurs.

STEP 3: Acyl group transfer to CoA. The proper arrow-pushing mechanism is shown in Figure 5.

Figure 5: Acyl group transfer to CoA
*NOTE: The reduced lipoyl arm now swings into the E3 active site, where Steps 4 and 5 occur.

STEP 4: Oxidation of the lipoyl moiety by the FAD coenzyme, as shown in Figure 6.

Figure 6: Oxidation of the lipoyl moiety by the FAD coenzyme.

STEP 5: Reoxidation of FADH2 to FAD, producing NADH:

FADH2 + NAD+ → FAD + NADH + H+

Disease relevance

A deficiency in any of the enzymes of this complex as well as an inhibition of the complex as a whole leads to a buildup of branched-chain amino acids and their harmful derivatives in the body. These accumulations lend a sweet smell to bodily excretions (such as ear wax and urine), leading to a pathology known as maple syrup urine disease.[19]

This enzyme is an

gluten sensitivity.[20]
Other mitochondrial autoantigens include
anti-mitochondrial antibodies
.

Mutations of the BCKDK gene, whose protein product controls the activity of the complex, may result in over-activation of the complex and excessive catabolism of the three amino acids. This leads to branched-chain keto acid dehydrogenase kinase deficiency, a rare disease first described in humans in 2012.[21]

References

  1. PMID 3597778
    .
  2. PMID 2649080
    .
  3. ISBN 978-0-07-182537-5
    .
  4. doi:10.1146/annurev.bi.35.070166.001311
    .
  5. PMID 3028049
    .
  6. PMID 4308861
    .
  7. PMID 14463994
    .
  8. PMID 10745006
    .
  9. S2CID 33210101
    .
  10. PMID 4055756
    .
  11. PMID 2188967
    .
  12. PMID 1888719
    .
  13. ^ Berg, Jeremy M., John L. Tymoczko, Lubert Stryer, and Lubert Stryer. Biochemistry. 6th ed. New York: W.H. Freeman, 2007. 481. Print.
  14. PMID 6652074
    .
  15. PMID 3800905
    .
  16. PMID 283398
    .
  17. PMID 6589597
    .
  18. ^ Berg, Jeremy M., John L. Tymoczko, Lubert Stryer, and Lubert Stryer. Biochemistry. 6th ed. New York: W.H. Freeman, 2007. 478-79. Print.
  19. S2CID 6426166
    .
  20. PMID 17657817
    .
  21. PMID 22956686
    .

External links
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