SDHA

Summary: IBA annotation for the overall SDH quinone reductase activity. GO:0008177 is defined as "the overall reaction of the entire SDH complex" (succinate + quinone -> fumarate + quinol). The IBA uses the qualifier 'enables' which is debatable for a single subunit of a complex enzyme. However, SDHA alone can catalyze the succinate -> fumarate half-reaction (the succinate dehydrogenase activity per se), and it is the catalytic subunit where the substrate binding and FAD-mediated oxidation occurs. The full quinone reduction requires all four subunits. The IMP annotation from PMID:7550341 uses 'contributes_to' which is arguably more precise for the full quinone-dependent reaction. Nevertheless, IBA annotations are well-curated phylogenetic inferences and the 'enables' qualifier is defensible since SDHA provides the primary catalytic function of the complex. The deep research review (SDHA-deep-research-falcon.md) confirms that the FAD cofactor is covalently linked in the SDHA subunit via a conserved histidine, essential for catalysis in characterized complex II enzymes.

Reason: SDHA is the catalytic subunit of SDH complex containing the FAD cofactor and active site for succinate oxidation. While the full quinone reduction requires the entire complex, SDHA's role is central and catalytic. The IBA is phylogenetically sound, but the enables qualifier should not be accepted as-is for the whole-complex quinone reaction. Use an intrinsic succinate dehydrogenase activity term for SDHA's enabled activity and retain GO:0008177 only with contributes_to.

Proposed replacements: succinate dehydrogenase activity

Summary: IBA annotation that SDHA is part of respiratory chain complex II. This is a core structural annotation for SDHA as the flavoprotein subunit of the SDH/Complex II heterotetramer (SDHA+SDHB+SDHC+SDHD). Confirmed by cryo-EM structure (PMID:37098072).

Reason: SDHA is unambiguously a subunit of Complex II. The cryo-EM structure at 2.86A shows all four subunits including SDHA in the complex (PMID:37098072). This is a core annotation.

Summary: IBA annotation for FAD binding. SDHA contains a covalently bound FAD cofactor attached at His99 (Tele-8alpha-FAD histidine). This is confirmed by crystal and cryo-EM structures (PMID:32887801, PMID:37098072). Note that GO:0071949 (FAD binding) is also annotated via Reactome. GO:0050660 is the more general term. Both are appropriate; this IBA is correct.

Reason: FAD binding is a core molecular function of SDHA. The FAD cofactor is covalently attached to His99 and is essential for catalysis. Supported by multiple structural studies.

Summary: IBA annotation for the specific biological process of electron transport from succinate to ubiquinone. This is the defining biological process for Complex II/SDH in the mitochondrial electron transport chain. SDHA initiates this process by oxidizing succinate via FAD and passing electrons through the iron-sulfur centers of SDHB to ubiquinone at SDHC/SDHD.

Reason: This is a core biological process annotation for SDHA. The electron flow from succinate to ubiquinone begins at SDHA's FAD cofactor. This is the defining ETC function of Complex II.

Summary: IBA annotation for electron transfer activity. SDHA is the initial electron acceptor in Complex II, receiving electrons from succinate via its FAD cofactor. The electrons then transfer through the [2Fe-2S] cluster of SDHB. This is a core molecular function annotation.

Reason: SDHA performs electron transfer as part of the succinate-to-ubiquinone chain. The FAD cofactor accepts electrons from succinate and transfers them to the iron-sulfur protein SDHB. This is phylogenetically and biochemically well-supported.

Summary: IEA annotation based on UniProt subcellular location mapping. SDHA is a peripheral membrane protein on the matrix side of the inner mitochondrial membrane, as part of Complex II. Confirmed by cryo-EM (PMID:37098072) and UniProt subcellular location annotation.

Reason: Correct localization. SDHA is the matrix-facing subunit of Complex II which is anchored in the inner mitochondrial membrane via SDHC and SDHD. The IEA mapping is accurate and consistent with experimental data including the cryo-EM structure.

Summary: IEA annotation for TCA cycle involvement. SDHA catalyzes step 6 of the TCA cycle: the oxidation of succinate to fumarate. This is one of the two core biological processes of Complex II (the other being ETC).

Reason: TCA cycle involvement is a core function of SDHA. The succinate to fumarate reaction is a canonical step of the TCA cycle. Widely supported by literature.

Summary: IEA annotation for the same SDH quinone activity as the IBA above, inferred from combined automated methods (UniProt keyword, InterPro, EC number). Redundant with the IBA and IMP annotations but consistent.

Reason: Consistent with Complex II function, but not acceptable as an enables annotation for SDHA alone. The quinone-dependent reaction is performed by the intact heterotetramer; SDHA's enabled activity is the succinate dehydrogenase half-reaction.

Proposed replacements: succinate dehydrogenase activity

Summary: IEA annotation for general oxidoreductase activity. SDHA catalyzes the oxidation of succinate (EC 1.3.5.1), making it an oxidoreductase. This is a correct but very broad parent term. The more specific child terms (GO:0008177, GO:0016627) are also annotated.

Reason: Correct but general. It is acceptable for IEA annotations to be broader than experimental annotations. The more specific GO:0008177 is also present.

Summary: IEA annotation from InterPro mapping. SDHA oxidizes succinate to fumarate, converting a CH-CH single bond to a C=C double bond. This is an accurate intermediate-level classification of the catalytic activity.

Reason: Correct classification. Succinate oxidation to fumarate involves removal of two hydrogens from the CH2-CH2 group to form the trans double bond of fumarate. This InterPro-based IEA is accurate.

Summary: IEA annotation for general electron transport chain involvement from InterPro. This is broader than GO:0006121 (mitochondrial electron transport, succinate to ubiquinone) which is the more specific IBA annotation. Both are correct.

Reason: Correct but more general than the IBA annotation GO:0006121. Complex II is part of the electron transport chain. Acceptable for IEA to use the broader term.

Summary: IEA annotation for FAD binding from InterPro. Redundant with the IBA annotation for the same term. Both are correct.

Reason: Correct and consistent with the IBA annotation. FAD is covalently bound to SDHA at His99.

Summary: IPI annotation from large-scale mass spectrometry protein-protein interaction study (Ewing et al. 2007). The WITH/FROM field indicates interaction with HLA-B (P01889). This is from a high-throughput screen and the biological significance of an SDHA-HLA-B interaction is unclear. Likely a non-specific or indirect detection.

Reason: High-throughput protein-protein interaction data. The SDHA-HLA-B interaction has no known biological relevance and is likely an artifact of overexpression-based mass spectrometry. Furthermore, 'protein binding' is uninformative as a GO term. Keep as non-core.

Summary: IPI annotation for interaction between SDHA and SDHAF2/SDH5 (Q9NX18). Hao et al. (2009) showed that SDH5/SDHAF2 is required for flavination of succinate dehydrogenase. The interaction between SDHA and SDHAF2 is essential for covalent FAD attachment. This is a biologically meaningful interaction confirmed by UniProt (INTERACTION section) and multiple studies.

Reason: The SDHA-SDHAF2 interaction is biologically meaningful (required for FAD cofactor insertion), but 'protein binding' is too vague. The interaction is better captured by the functional context (SDHAF2 is a complex II assembly factor). Keep as non-core since the underlying biology is valid even though the GO term is uninformative.

Summary: IPI annotation for interaction with SDHB (P21912) from LC-MS/MS analysis of blue native PAGE-separated complexes. This confirms the well-established SDHA-SDHB interaction as part of Complex II assembly.

Reason: The SDHA-SDHB interaction is a core biochemical feature of Complex II, but this is already captured by the CC annotation GO:0045273 (part_of respiratory chain complex II). The 'protein binding' annotation is uninformative. Keep as non-core.

Summary: IPI annotation for interaction with SDHB (P21912) from a study on cochaperone binding to LYR motifs for iron-sulfur cluster delivery. This relates to Complex II assembly.

Reason: Another SDHA-SDHB interaction detected in the context of iron-sulfur cluster delivery. Biologically relevant to Complex II assembly but 'protein binding' is uninformative.

Summary: IPI annotation for interaction with SDHAF2 (Q9NX18) from a quantitative interactome study (Hein et al. 2015). Confirms the SDHA-SDHAF2 assembly factor interaction.

Reason: Confirms the SDHA-SDHAF2 interaction in an independent quantitative study. Biologically relevant but 'protein binding' remains uninformative as a GO term.

Summary: IPI annotation for interaction with CFTR (P13569) from a study on deltaF508-CFTR interactome remodelling. The biological significance of SDHA-CFTR interaction is questionable -- this is likely a non-specific detection in a large-scale study.

Reason: The SDHA-CFTR interaction is of unclear biological significance. CFTR is an ABC transporter involved in chloride conductance, and its interaction with a mitochondrial enzyme is likely indirect or an artifact. Keep as non-core.

Summary: IPI annotation for interaction with SDHB (P21912) from a study on SDHAF1 mutations impairing Fe-S cluster transfer to SDHB. Relevant to Complex II assembly.

Reason: SDHA-SDHB interaction confirmed in the context of Fe-S cluster assembly. Biologically meaningful but 'protein binding' is uninformative. Already captured by CC annotation.

Summary: IPI annotation for interaction with PTPN3 (P26045) from systematic analysis of human protein phosphatase interactions. The biological relevance of an SDHA-PTPN3 interaction is unclear. PTPN3 is a tyrosine phosphatase. SDHA is known to be phosphorylated at Tyr-215 by SRC, so a phosphatase interaction could be biologically relevant but is not well characterized.

Reason: High-throughput phosphatase interaction study. While SDHA is phosphorylated at Y215, the specific relevance of PTPN3 interaction is not established.

Summary: IPI annotation for interaction with SDHB (P21912) from architecture of the human interactome study (Huttlin et al. 2017). Confirms SDHA-SDHB subunit interaction.

Reason: Another confirmation of the SDHA-SDHB interaction. Already well established and captured by the CC annotation for Complex II membership.

Summary: IPI annotation for interaction with SDHAF2 (Q9NX18) from the same architecture of the human interactome study (Huttlin et al. 2017). This is the second GOA entry for this PMID, detecting the SDHA-SDHAF2 assembly factor interaction.

Reason: Confirms the SDHA-SDHAF2 interaction. SDHAF2 is the assembly factor required for FAD insertion into SDHA. Biologically meaningful but 'protein binding' is uninformative.

Summary: IPI annotation for interaction with HLA-B (P01889) from mitochondrial protein interaction map linked to neurodegeneration. Same interactor as PMID:17353931. The biological significance of SDHA-HLA-B interaction remains unclear.

Reason: Second independent detection of SDHA-HLA-B interaction, but the biological relevance remains unclear. HLA-B is an MHC class I molecule, not expected to functionally interact with a mitochondrial matrix enzyme.

Summary: IPI annotation for interaction with CFTR (P13569) from a proteomic variant approach study. Second SDHA-CFTR interaction, of unclear biological significance.

Reason: SDHA-CFTR interaction detected by proteomics. Unclear biological significance.

Summary: IPI annotation for interaction with CFTR (P13569) from study on calpain 1 and Phe508del-CFTR. Third SDHA-CFTR interaction detection. Multiple detections suggest a real physical interaction but its functional significance for SDHA is unclear.

Reason: Third detection of SDHA-CFTR interaction. While multiple detections suggest a real interaction, the functional significance for SDHA function is unclear.

Summary: IPI annotation for interaction with SDHB (P21912) from dual proteome-scale network study (Huttlin et al. 2021). Confirms the known Complex II SDHA-SDHB subunit interaction.

Reason: Confirms the SDHA-SDHB interaction. Well established and captured by CC annotation.

Summary: IPI annotation for interaction with SDHAF2 (Q9NX18) from dual proteome-scale network study (Huttlin et al. 2021). This is the second GOA entry for this PMID, confirming the SDHA-SDHAF2 assembly factor interaction.

Reason: Confirms the SDHA-SDHAF2 interaction. Well established.

Summary: IPI annotation for interaction with CFTR (P13569) from membrane two-hybrid screening. Fourth SDHA-CFTR interaction detection.

Reason: Yet another SDHA-CFTR detection. While robust, CFTR interaction is not relevant to the core function of SDHA.

Summary: IEA annotation for mitochondrial localization via Ensembl Compara ortholog transfer. SDHA has a mitochondrial transit peptide (residues 1-42) and is localized to the mitochondrial matrix as part of Complex II.

Reason: Correct localization, well supported by multiple lines of evidence including the transit peptide and IDA evidence.

Summary: IEA annotation for mitochondrial matrix localization via Ensembl Compara ortholog transfer. SDHA faces the matrix side of the inner membrane as a peripheral membrane protein.

Reason: Correct. SDHA is on the matrix side of the inner mitochondrial membrane, confirmed by cryo-EM structure (PMID:37098072) showing SDHA in the hydrophilic head of Complex II facing the matrix.

Summary: IEA annotation for Complex II membership via Ensembl Compara ortholog transfer. Redundant with IBA and other annotations for the same term.

Reason: Correct and consistent with IBA, ISS, IDA, and TAS annotations for this term.

Summary: IDA annotation for mitochondrial localization from HPA immunofluorescence data. Direct experimental evidence of SDHA mitochondrial localization.

Reason: Direct experimental evidence of mitochondrial localization by immunofluorescence.

Summary: TAS annotation from Reactome TCA cycle pathway. SDHA participates in the TCA cycle by catalyzing the succinate to fumarate step.

Reason: Core function annotation. Consistent with IEA and NAS annotations for the same term. SDHA is a canonical TCA cycle enzyme.

Summary: NAS annotation from ComplexPortal based on review by Signes and Fernandez-Vizarra (2018) on assembly of OXPHOS complexes. SDHA is part of Complex II which is embedded in the inner mitochondrial membrane.

Reason: Correct localization. Complex II spans the inner membrane via SDHC/SDHD subunits, with SDHA on the matrix side as a peripheral membrane protein.

Summary: NAS annotation from ComplexPortal for TCA cycle involvement. Redundant with other TCA cycle annotations but consistent.

Reason: Correct and consistent with other TCA cycle annotations from Reactome and IEA sources.

Summary: NAS annotation from ComplexPortal for the specific ETC process. Consistent with the IBA annotation for the same term.

Reason: Correct. This is a core biological process for SDHA/Complex II.

Summary: NAS annotation from ComplexPortal suggesting SDHA is involved in proton motive force-driven mitochondrial ATP synthesis. This annotation is problematic because Complex II does NOT pump protons across the inner mitochondrial membrane. Unlike Complexes I, III, and IV which translocate protons to generate the proton motive force, Complex II transfers electrons from succinate to ubiquinone without any proton pumping. Complex II contributes to ATP synthesis only indirectly by feeding reduced ubiquinol into the Q pool, which is then oxidized by Complex III (which does pump protons). Annotating SDHA with this term conflates electron donation to the Q pool with proton translocation.

Reason: Complex II is the only OXPHOS complex that does NOT pump protons. The proton motive force is generated by Complexes I, III, and IV. Complex II feeds electrons into the ubiquinone pool but does not directly contribute to the proton gradient. This annotation is misleading and should be removed. The correct process annotation for SDHA is GO:0006121 (mitochondrial electron transport, succinate to ubiquinone).

Summary: TAS annotation from Reactome for FAD binding. The Reactome entry R-HSA-9854672 describes the covalent attachment of FAD to SDHA. GO:0071949 (FAD binding) specifically refers to binding the oxidized form of FAD, which is appropriate for SDHA.

Reason: Correct. SDHA covalently binds FAD at His99. This is the more specific FAD binding term compared to GO:0050660, and both are appropriate. Reactome accurately captures this step of Complex II maturation.

Summary: HTP annotation for mitochondrial localization from a quantitative high-confidence human mitochondrial proteome study (Morgenstern et al. 2021). SDHA was identified in the mitochondrial proteome.

Reason: Correct. SDHA is a well-established mitochondrial protein confirmed by proteomics.

Summary: ISS annotation for Complex II membership by manual transfer from bovine ortholog (Q0QF01). Consistent with all other annotations for this term.

Reason: Correct. Transfer from the well-characterized bovine SDH complex.

Summary: IMP annotation with 'contributes_to' qualifier from the landmark Bourgeron et al. (1995) study. This study identified the first nuclear gene mutation causing mitochondrial respiratory chain deficiency -- an Arg554Trp mutation in SDHA causing Leigh syndrome with complex II deficiency. The 'contributes_to' qualifier is appropriate for GO:0008177 since the GO term definition states "This term represents the overall reaction of the entire SDH complex." The full quinone reduction reaction requires all four subunits (SDHA provides succinate oxidation/FAD reduction, SDHB provides Fe-S electron relay, and SDHC/SDHD provide the quinone binding site). SDHA alone cannot complete the quinone reduction half of the reaction.

Reason: The 'contributes_to' qualifier is arguably more precise than 'enables' for GO:0008177 since the GO definition explicitly states it represents the overall reaction of the entire complex. SDHA provides the succinate dehydrogenase half-reaction (via FAD) but quinone reduction requires the membrane-anchored subunits. The contributes_to qualifier is correct for this complex-level activity; the intrinsic SDHA activity is covered separately by the proposed GO:0000104 annotation.

Summary: IDA annotation for Complex II membership from the cryo-EM structure study (Du et al. 2023). This study resolved the human Complex II structure at 2.86A showing all four subunits. SDHA was directly identified in the complex by cryo-EM, SDS-PAGE, and mass spectrometry.

Reason: Direct experimental evidence from cryo-EM structure of human Complex II showing SDHA as a subunit.

Summary: TAS annotation from Reactome for mitochondrial matrix localization. The Reactome entry describes the SDH complex dehydrogenation of succinate, placing SDHA in the matrix.

Reason: Correct. SDHA is on the matrix face of Complex II.

Summary: TAS from Reactome for matrix localization, associated with the FAD attachment to SDHA reaction which occurs in the matrix.

Reason: Correct. FAD attachment to SDHA occurs in the mitochondrial matrix.

Summary: TAS from Reactome for matrix localization, associated with SDHAF4 binding to FAD-SDHA.

Reason: Correct. SDHAF4 binding to FAD-SDHA occurs in the mitochondrial matrix during Complex II assembly.

Summary: TAS from Reactome for matrix localization, associated with SDHA binding to SDHB.

Reason: Correct. SDHA-SDHB subcomplex formation occurs in the matrix.

Summary: TAS from Reactome for matrix localization, associated with SDHA:SDHB binding to SDHC:SDHD.

Reason: Correct. The final assembly step of Complex II involves SDHA:SDHB joining SDHC:SDHD at the membrane.

Summary: IMP annotation from Renkema et al. (2015) who characterized SDHA mutations causing multisystem mitochondrial disease. They showed that the c.565T>G mutation severely affects enzyme activity and confirmed pathogenicity by lentiviral complementation. This annotation uses 'enables' qualifier (no explicit 'contributes_to' in GOA TSV line).

Reason: Valid IMP evidence showing that SDHA mutations directly impair SDH enzyme activity. The study demonstrates that specific SDHA mutations cause isolated complex II deficiency through impaired catalysis, but the enabled MF should be the intrinsic succinate dehydrogenase activity rather than the whole-complex quinone activity unless the qualifier is contributes_to.

Proposed replacements: succinate dehydrogenase activity

Summary: IPI annotation for interaction with TRAP1 (Q12931) from Sciacovelli et al. (2013). This study showed that the mitochondrial chaperone TRAP1 binds to and inhibits SDH complex (specifically SDHA), leading to succinate accumulation and pseudohypoxic HIF1a stabilization in tumors. This is a functionally significant interaction demonstrated by co-immunoprecipitation, BN-PAGE, and crosslinking experiments.

Reason: The SDHA-TRAP1 interaction is biologically significant (TRAP1 inhibits SDH activity to promote the Warburg effect in tumors), but 'protein binding' remains uninformative. The interaction is regulatory rather than a core molecular function of SDHA.

Summary: ISS annotation for inner membrane localization by transfer from bovine ortholog (Q0QF01). Consistent with other annotations and cryo-EM evidence.

Reason: Correct. Transfer from well-characterized bovine SDH complex.

Summary: IPI annotation for interaction with frataxin (Q16595) from Gonzalez-Cabo et al. (2005). This study showed physical interaction between human frataxin and human succinate dehydrogenase complex subunits, suggesting a role for frataxin in the mitochondrial electron transport chain. Frataxin is involved in iron-sulfur cluster biogenesis.

Reason: The SDHA-frataxin interaction is biologically interesting given frataxin's role in Fe-S cluster biogenesis and Friedreich ataxia pathogenesis. However, 'protein binding' is uninformative and this represents a regulatory/assembly interaction rather than a core SDHA function.

Summary: IDA annotation for succinate metabolic process from Bourgeron et al. (1995). SDHA catalyzes the oxidation of succinate to fumarate, which is central to succinate metabolism. This is correct but less specific than the TCA cycle annotation.

Reason: Correct. SDHA directly metabolizes succinate as part of its catalytic function. This is a reasonable biological process annotation complementing the TCA cycle and ETC annotations.

Summary: IMP annotation for nervous system development from Horvath et al. (2006). This study described a child with Leigh syndrome caused by compound heterozygous SDHA mutations (W119X and A83V), presenting with severe progressive neurodegenerative disorder causing epilepsy, psychomotor retardation, and tetraspasticity starting at age five months. The IMP logic is that SDHA mutations cause a neurodevelopmental phenotype, therefore SDHA is involved in nervous system development. However, this is a classic case of over-annotation. SDHA is a housekeeping metabolic enzyme. The nervous system is particularly sensitive to mitochondrial dysfunction due to its high energy demands, but SDHA is not specifically involved in nervous system development. The neurological phenotype is a secondary consequence of impaired cellular energy production, not a direct developmental role for SDHA in neural patterning or differentiation.

Reason: This is a clear over-annotation. SDHA mutations cause Leigh syndrome with neurological features because the nervous system is especially vulnerable to mitochondrial energy deficits, not because SDHA has a specific role in neural development. The nervous system phenotype is a secondary consequence of impaired oxidative phosphorylation. By this logic, any essential metabolic gene causing disease with neurological symptoms would be annotated with 'nervous system development', which is not informative.

Summary: IDA annotation for respiratory electron transport chain from Bourgeron et al. (1995). The study showed that SDHA mutation causes complex II deficiency, directly demonstrating SDHA's role in the respiratory electron transport chain. This is broader than GO:0006121 but still accurate.

Reason: Correct. SDHA is part of Complex II which is a component of the respiratory electron transport chain. The Bourgeron et al. study directly demonstrated that SDHA mutation leads to respiratory chain deficiency.

Summary: IDA annotation for mitochondrial localization from Huang et al. (2007). This study was about Complex I and IFN-beta/RA-induced cell death. The connection to SDHA mitochondrial localization is indirect -- the study mentions upregulation of MRC complex subunits but is primarily about Complex I (GRIM-19, NDUFS3). SDHA mitochondrial localization is well-established from other sources regardless.

Reason: Mitochondrial localization of SDHA is beyond question, even though this particular reference is not the strongest evidence for SDHA specifically.

Summary: IDA annotation for mitochondrial localization from Bourgeron et al. (1995). The study demonstrated mitochondrial respiratory chain deficiency from SDHA mutation, placing SDHA in the mitochondrion.

Reason: Correct mitochondrial localization, supported by the original study showing that SDHA mutation causes mitochondrial respiratory chain deficiency.

Summary: TAS annotation for TCA cycle from Bourgeron et al. (1995). The study refers to SDH as part of the TCA cycle/respiratory chain.

Reason: Correct. The succinate to fumarate reaction is a canonical TCA cycle step.

Summary: TAS annotation for Complex II membership from Bourgeron et al. (1995). The study directly discusses Complex II deficiency from SDHA mutation.

Reason: Correct. SDHA is the flavoprotein subunit of Complex II.

Summary: GO:0000104 (succinate dehydrogenase activity) is defined as "Catalysis of the reaction: succinate + acceptor = fumarate + reduced acceptor." This is a more appropriate molecular function term for SDHA than GO:0008177 (quinone-specific) when annotating the subunit alone, because SDHA catalyzes the succinate to fumarate reaction via its FAD cofactor regardless of the downstream electron acceptor. The Bourgeron et al. study demonstrated that mutation of SDHA impairs succinate dehydrogenase activity. This annotation should use the 'enables' qualifier since SDHA alone (with its FAD cofactor) is sufficient to catalyze succinate oxidation.

Reason: GO:0000104 more precisely captures SDHA's intrinsic catalytic function (succinate oxidation with a generic acceptor) as opposed to GO:0008177 which specifies the quinone-dependent overall complex reaction. SDHA alone can oxidize succinate to fumarate; the FAD cofactor serves as the immediate electron acceptor. This term fills a gap where the current annotations only capture the complex-level activity. Note: GO:0160308 (succinate dehydrogenase (FAD) activity; RHEA:30343) is a more specific child term that explicitly names FAD as the acceptor (FAD + succinate + H+ = fumarate + FADH2). This may be more precise for SDHA since FAD is the actual cofactor. However, GO:0160308 is under consideration for obsolescence. If retained, it would be the preferred term over GO:0000104. The three SDH activity terms form a specificity series: GO:0000104 (generic acceptor, RHEA:16357) > GO:0160308 (FAD, RHEA:30343) and GO:0008177 (quinone, EC:1.3.5.1, RHEA:40523).