Maple Syrup Urine Disease

Stable Identifier
R-HSA-9865114
Type
Pathway
Species
Homo sapiens
ReviewStatus
5/5
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Maple Syrup Urine Disease
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The branched-chain alpha ketoacid dehydrogenase complex (BCKDH) catalyzes the oxidative decarboxylation of branched-chain keto acids in the mitochondrial matrix as the second step in the degradation of branched-chain amino acids (BCAAs) leucine, valine and isoleucine, providing acetyl CoA and succinyl CoA intermediates for the Krebs Cycle (reviewed in Strauss et al, 2020; Zhang et al, 2023).
BCKDH is a multi-enzyme complex consisting of three sub-complexes, the E2 transacylase, the E1 decarboxylase and the E3 dehydrogenase. The core of BCKDH is the E2 transacylase domain, made up of 24 copies of Dihydrolipoamide Branched-chain Transacylase (DBT) arranged in octahedral symmetry. Surrounding the E2 core are 12 copies of the E1 decarboxylase tetramer (each of which consists of a dimer of BCKDHA and a dimer of BCKDHB) and six copies of the E3 dehydrogenase (each consisting of a dimer of Dihydrolipoyl Dehydrogenase (DLD)). The E3 subcomplex is not specific to BCKDH but is also a component of the pyruvate dehydrogenase complex (PDC) and the alpha-ketoglutarate dehydrogenase complex (alpha-KGDC) (Chang et al, 2002; Brautigam et al, 2005; Aevarsson et al, 2000; reviewed in Biswas et al, 2019; Strauss et al, 2020).
In addition to the E1, E2 and E3 components, the BCKDH complex also depends on other cofactors- lipoamide for the function of the E2 transacylase, thiamine diphosphate and potassium for the function of the E1 decarboxylase and FAD and NAD+ for the function of the E3 dehydrogenase (Chang et al, 2002; Brautigam et al, 2005; Aevarsson et al, 2000; reviewed in Biswas et al, 2019; Strauss et al, 2020).
The activity of BCKDH is regulated by the association of BCKD kinase (BCKDK) and protein phosphatase 1K (PPM1K) with the macromolecular complex (Reed et al, 1985). Phosphorylation of BCKDHB S342 by BCKDK inhibits the catalytic activity of BCKDH, while PPM1K-mediated dephosphorylation activates it (Li et al, 2004; Wynn et al, 2004; Wynn et al, 2012). BCKDK is itself negatively regulated by thiamine (Chuang et al, 2006).
Structures for each of the subcomplexes of human BCKDH have been solved, and the complex has a total molecular mass on the order of 4 million Da (Chang et al, 2002; Brautigam et al, 2005; Aevarsson et al, 2000).
Loss-of-function mutations in the BCKDHA, BCKDHB and DBT genes disrupt the stability and the activity of the BCKDH complex, causing an accumulation of branched-chain keto-acids that causes the characteristic odor associated with Maple Syrup Urine disease (MSUD), an inborn error of metabolism with a prevalence of 1:185,000 live births (reviewed in Strauss et al, 2020; Biswas et al, 2019). MSUD is an autosomal recessive disorder and in its classic neonatal form is characterized by a maple syrup odor to the urine, poor feeding, mental and physical retardation, lethargy, seizures, coma and death. Classic MSUD, like the intermediate, intermittent and thiamine-responsive forms described below, may arise as a result of mutations in any of BCKDHA, BCKDHB or DBT. Classic MSUD is characterized by the lowest (~0-3%) residual enzymatic activity of all the forms, and presents clinically during the neonatal period. An intermediate form (residual activity ~3-30%) manifests clinically many months after birth with signs of mental retardation and developmental delay. Patients with the intermittent form of MSUD have normal levels of BCAA and BCKA and normal development and physiology while healthy, but are triggered into manifesting symptoms of MSUD when stressed by, for instance, infection. The existence of a thiamine-responsive form of MSUD, in which symptoms are alleviated by dietary thiamine, is somewhat controversial, but may reflect the inhibitory effect of thiamine on BCKDK, relieving inhibition of BCKDH activity (Chaung et al, 2006; reviewed in Strauss et al, 2020, Biswas et al, 2019). Mandatory newborn screening programs include testing for MSUD, allowing for early intervention that is especially critical in cases of classic MSUD (Strauss et al, 2020)
Mutations in DLD, the E3 subunit shared with PDH and alpha-KGDH, affect the enzymatic activity of all three complexes and are responsible for a more severe disorder called dihydrolipoamide dehydrogenase deficiency (DLDD). DLLD generally results in death in infancy due to lactic acidosis (Taylor et al, 1978; reviewed in Ambrus, 2019).
Literature References
PubMed ID Title Journal Year
37432261 Branched-Chain Amino Acids Metabolism and Their Roles in Retinopathy: From Relevance to Mechanism

Zhang, X, Xia, M, Wu, Y, Zhang, F

Nutrients 2023
15166214 Cross-talk between thiamin diphosphate binding and phosphorylation loop conformation in human branched-chain alpha-keto acid decarboxylase/dehydrogenase

Li, J, Wynn, RM, Machius, M, Chuang, JL, Karthikeyan, S, Tomchick, DR, Chuang, DT

J. Biol. Chem. 2004
15576032 Molecular mechanism for regulation of the human mitochondrial branched-chain alpha-ketoacid dehydrogenase complex by phosphorylation

Wynn, RM, Kato, M, Machius, M, Chuang, JL, Li, J, Tomchick, DR, Chuang, DT

Structure 2004
20301495 Maple Syrup Urine Disease

Strauss, KA, Puffenberger, EG, Carson, VJ

2006
3004826 Regulation of mammalian pyruvate and branched-chain alpha-keto acid dehydrogenase complexes by phosphorylation-dephosphorylation

Reed, LJ, Damuni, Z, Merryfield, ML

Curr Top Cell Regul 1985
15946682 Crystal structure of human dihydrolipoamide dehydrogenase: NAD+/NADH binding and the structural basis of disease-causing mutations

Brautigam, CA, Chuang, JL, Tomchick, DR, Machius, M, Chuang, DT

J Mol Biol 2005
10745006 Crystal structure of human branched-chain alpha-ketoacid dehydrogenase and the molecular basis of multienzyme complex deficiency in maple syrup urine disease.

Aevarsson, A, Chuang, JL, Wynn, RM, Turley, S, Chuang, DT, Hol, WG

Structure Fold Des 2000
31084571 Role of branched-chain amino acid-catabolizing enzymes in intertissue signaling, metabolic remodeling, and energy homeostasis

Biswas, D, Duffley, L, Pulinilkunnil, T

FASEB J 2019
11839747 Solution structure and dynamics of the lipoic acid-bearing domain of human mitochondrial branched-chain alpha-keto acid dehydrogenase complex

Chang, CF, Chou, HT, Chuang, JL, Chuang, DT, Huang, TH

J Biol Chem 2002
22291014 Structural and biochemical characterization of human mitochondrial branched-chain α-ketoacid dehydrogenase phosphatase

Wynn, RM, Li, J, Brautigam, CA, Chuang, JL, Chuang, DT

J. Biol. Chem. 2012
Participants
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as an event of
Disease
Name Identifier Synonyms
maple syrup urine disease DOID:9269 dihydrolipoamide dehydrogenase deficiency
Cross References
Mondo
Authored
Rothfels, K  (2024-07-29)
Reviewed
D'Eustachio, P  (2024-08-18)
Created
Rothfels, K  (2024-03-08)
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