Deficiency Disorders of Components of PDH Complex: E2, E3, and E3BP Deficiencies

Introduction...................................................................................................... 376 Clinical Deficiency of PDHc ....................................................................... 376

E2 (Dihydrolipoamide Transacetylase)............................................................ 377 Structure of E2 Protein ................................................................................ 378 Genetic Mutations Causing E2 Deficiency.................................................. 379 Effect of E2 Mutations on PDHc Structure and Function........................... 381

E3 (Dihydrolipoamide Dehydrogenase) .......................................................... 382 Structure of E3 Protein ................................................................................ 382 Genetic Mutations Causing E3 Deficiency.................................................. 383 Clinical Outcome of E3 Deficiency............................................................. 383 Genetic Heterogeneity in E3-Deficient Patients .......................................... 384 Mutations in FAD Domain (Amino Acids 35-184)................................ 384 Mutations in NAD Domain (Amino Acids 185-317) ............................. 384 Mutations in Central Domain (Amino Acids 318-385) .......................... 389 Mutations in Homodimer Interface Domain (Amino Acids 386-509) ... 389 Mutations Creating Null Alleles .............................................................. 390

Clinical Consequences for Heterozygote Carrier Parents............................ 391 Therapy for E3 Deficiency........................................................................... 391

E3-Binding Protein .......................................................................................... 392 Structure of E3BP Protein ........................................................................... 392 Genetic Mutations Causing E3BP Deficiency............................................. 393 Nature of Genetic Mutations Causing E3BP Deficiency ............................ 394 E3BP Deficiency Leads to Reduced mRNA Transcripts and Loss of Protein Product ........................................................................................ 397

Parental Carrier Status Shows Variable Clinical Phenotypes...................... 398 Clinical Symptoms of E3BP Deficiency ..................................................... 398

Conclusion ....................................................................................................... 399 Abbreviations ................................................................................................... 399 References ........................................................................................................ 400

The pyruvate dehydrogenase complex (PDHc) is a multimeric enzyme comprising several catalytic subunits and cofactors. The enzyme links the glycolytic and tricarboxylic acid pathways by decarboxylating pyruvate to acetyl coenzyme A. The first enzymatic component of the complex is E1 (pyruvate decarboxylase), a heterotetramer of two a and two b subunits. The activity of E1 is regulated by the phosphorylation state of three conserved serine residues of the E1a subunit. This reversible modification of E1a is catalyzed by two enzymes, pyruvate dehydrogenase kinase (PDK) and pyruvate dehydrogenase phosphatase (PDP), which inactivate and activate the complex, respectively (Reed 1981). Thiamine pyrophosphate is non-covalently bound to this first component and is critical for both the decarboxylation of pyruvate and the reductive transfer of the acetyl group to the multi-domained E2 component (dihydrolipoamide transacetylase). The inner catalytic domain of E2 forms the major structural core of the PDH complex; two lipoyl domains catalyze the transfer of the acetyl group to CoA and the E1-binding domain is responsible for the binding of the E1 component to the complex. The E3-binding protein (E3BP) is a minor constituent of the structural core, which is required to anchor the E3 homodimer component (dihydrolipoamide dehydrogenase) to the complex. The E3 dimer contains two flavin adenine dinucleotide (FAD) molecules required to reoxidize the dihydrolipoyl moiety of E2. FADH2 is then oxidized by NAD

þ to complete the catalytic events of the complex (Figure 15.1).