Lipoic acid synthetase / LIAS

evidence_span

{"source_cache": "artifacts/ala-research/40640146.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "292f83149906d0c3be473ce3b23be4ee13d1c662b2665993808021098523cd23", "start_char": 0, "end_char": 953, "text_sha256": "292f83149906d0c3be473ce3b23be4ee13d1c662b2665993808021098523cd23"}

experimental_model

X-ray structures of catalytic stages with human lipoyl synthase

exposure

Structural trapping of sulfur-insertion intermediates

limitations

Structural snapshots establish reaction intermediates, not clinical nutrient requirements.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human recombinant proteins

plain_language

LIAS turns the attached precursor into a sulfur-bearing working cofactor.

primary_references

[ala-p40640146] Structural basis for catalysis by human lipoyl synthase. (2025). https://pubmed.ncbi.nlm.nih.gov/40640146/ DOI: 10.1038/s41467-025-61393-x

tissue_or_cell_type

LIAS and H-protein substrate

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 260–271

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray structures of catalytic stages with human lipoyl synthase · source_derived_draft · unverified_draft

### ala-lias-sulfur-installation LIAS installs sulfur at carbon 6 and carbon 8 of an octanoyl-lysyl residue on GCSH. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: LIAS turns the attached precursor into a sulfur-bearing working cofactor. organism: Human recombinant proteins tissue_or_cell_type: LIAS and H-protein substrate experimental_model: X-ray structures of catalytic stages with human lipoyl synthase limitations: Structural snapshots establish reaction intermediates, not clinical nutrient requirements. exposure: Structural trapping of sulfur-insertion intermediates evidence_span: {"source_cache": "artifacts/ala-research/40640146.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "292f83149906d0c3be473ce3b23be4ee13d1c662b2665993808021098523cd23", "start_char": 0, "end_char": 953, "text_sha256": "292f83149906d0c3be473ce3b23be4ee13d1c662b2665993808021098523cd23"} [ala-p40640146] Structural basis for catalysis by human lipoyl synthase. (2025). https://pubmed.ncbi.nlm.nih.gov/40640146/ DOI: 10.1038/s41467-025-61393-x

evidence_span

{"source_cache": "artifacts/ala-research/40640146.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "292f83149906d0c3be473ce3b23be4ee13d1c662b2665993808021098523cd23", "start_char": 0, "end_char": 953, "text_sha256": "292f83149906d0c3be473ce3b23be4ee13d1c662b2665993808021098523cd23"}

experimental_model

X-ray structures of catalytic stages with human lipoyl synthase

exposure

Structural trapping of sulfur-insertion intermediates

limitations

Structural snapshots establish reaction intermediates, not clinical nutrient requirements.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human recombinant proteins

plain_language

One sulfur-insertion intermediate temporarily links the enzyme, its iron-sulfur cluster and its substrate.

primary_references

[ala-p40640146] Structural basis for catalysis by human lipoyl synthase. (2025). https://pubmed.ncbi.nlm.nih.gov/40640146/ DOI: 10.1038/s41467-025-61393-x

tissue_or_cell_type

LIAS and H-protein substrate

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 273–284

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · X-ray structures of catalytic stages with human lipoyl synthase · source_derived_draft · unverified_draft

### ala-lias-trapped-intermediate Crystallography captured LIAS cross-linked to its H-protein substrate through a 6-mercaptooctanoyl ligand at a [3Fe-4S] cluster. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: One sulfur-insertion intermediate temporarily links the enzyme, its iron-sulfur cluster and its substrate. organism: Human recombinant proteins tissue_or_cell_type: LIAS and H-protein substrate experimental_model: X-ray structures of catalytic stages with human lipoyl synthase limitations: Structural snapshots establish reaction intermediates, not clinical nutrient requirements. exposure: Structural trapping of sulfur-insertion intermediates evidence_span: {"source_cache": "artifacts/ala-research/40640146.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "292f83149906d0c3be473ce3b23be4ee13d1c662b2665993808021098523cd23", "start_char": 0, "end_char": 953, "text_sha256": "292f83149906d0c3be473ce3b23be4ee13d1c662b2665993808021098523cd23"} [ala-p40640146] Structural basis for catalysis by human lipoyl synthase. (2025). https://pubmed.ncbi.nlm.nih.gov/40640146/ DOI: 10.1038/s41467-025-61393-x

evidence_span

{"source_cache": "artifacts/ala-research/36281303.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f", "start_char": 0, "end_char": 1732, "text_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f"}

experimental_model

Purified human LIAS turnover and cluster-transfer assays

exposure

LIAS with candidate iron-sulfur cluster donors

limitations

Cell-free transfer distinguishes direct donor activity from upstream functions in intact cells.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human recombinant proteins

plain_language

Two iron-sulfur clusters perform different jobs in the same enzyme.

primary_references

[ala-p36281303] In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1. (2022). https://pubmed.ncbi.nlm.nih.gov/36281303/ DOI: 10.1021/acsbiomedchemau.2c00020

tissue_or_cell_type

Mitochondrial lipoyl synthesis machinery

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 299–310

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human LIAS turnover and cluster-transfer assays · source_derived_draft · unverified_draft

### ala-lias-two-clusters LIAS has distinct radical-SAM and auxiliary [4Fe-4S] clusters; the latter supplies sulfur during lipoyl synthesis. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Two iron-sulfur clusters perform different jobs in the same enzyme. organism: Human recombinant proteins tissue_or_cell_type: Mitochondrial lipoyl synthesis machinery experimental_model: Purified human LIAS turnover and cluster-transfer assays limitations: Cell-free transfer distinguishes direct donor activity from upstream functions in intact cells. exposure: LIAS with candidate iron-sulfur cluster donors evidence_span: {"source_cache": "artifacts/ala-research/36281303.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f", "start_char": 0, "end_char": 1732, "text_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f"} [ala-p36281303] In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1. (2022). https://pubmed.ncbi.nlm.nih.gov/36281303/ DOI: 10.1021/acsbiomedchemau.2c00020

evidence_span

{"source_cache": "artifacts/ala-research/33562493.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4261f63098ce640cc87368d3f23f294441fdfa2a3f9b271086821fc1196bb3ac", "start_char": 0, "end_char": 1544, "text_sha256": "4261f63098ce640cc87368d3f23f294441fdfa2a3f9b271086821fc1196bb3ac"}

experimental_model

Recombinant human LIAS cluster reconstitution, EPR and LC-MS

exposure

[2Fe-2S]-loaded ISCU or ISCA2 donors

limitations

In vitro donor capacity does not establish a unique physiological donor or exclude other routes.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human proteins

plain_language

These carrier proteins can help rebuild active enzyme under assay conditions.

primary_references

[ala-p33562493] Characterization and Reconstitution of Human Lipoyl Synthase (LIAS) Supports ISCA2 and ISCU as Primary Cluster Donors and an Ordered Mechanism of Cluster Assembly. (2021). https://pubmed.ncbi.nlm.nih.gov/33562493/ DOI: 10.3390/ijms22041598

tissue_or_cell_type

Two LIAS iron-sulfur sites

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 390–401

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant human LIAS cluster reconstitution, EPR and LC-MS · source_derived_draft · unverified_draft

### ala-iscu-isca2-reconstitution [2Fe-2S]-loaded human ISCU and ISCA2 reconstituted catalytically active human LIAS in vitro. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: These carrier proteins can help rebuild active enzyme under assay conditions. organism: Human proteins tissue_or_cell_type: Two LIAS iron-sulfur sites experimental_model: Recombinant human LIAS cluster reconstitution, EPR and LC-MS limitations: In vitro donor capacity does not establish a unique physiological donor or exclude other routes. exposure: [2Fe-2S]-loaded ISCU or ISCA2 donors evidence_span: {"source_cache": "artifacts/ala-research/33562493.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "4261f63098ce640cc87368d3f23f294441fdfa2a3f9b271086821fc1196bb3ac", "start_char": 0, "end_char": 1544, "text_sha256": "4261f63098ce640cc87368d3f23f294441fdfa2a3f9b271086821fc1196bb3ac"} [ala-p33562493] Characterization and Reconstitution of Human Lipoyl Synthase (LIAS) Supports ISCA2 and ISCU as Primary Cluster Donors and an Ordered Mechanism of Cluster Assembly. (2021). https://pubmed.ncbi.nlm.nih.gov/33562493/ DOI: 10.3390/ijms22041598

evidence_span

{"source_cache": "artifacts/ala-research/35343688.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "62b2b8ddcff12b7264515cd251238a0f0e4dbe086fa72830ebff6e88f5db0689", "start_char": 0, "end_char": 670, "text_sha256": "62b2b8ddcff12b7264515cd251238a0f0e4dbe086fa72830ebff6e88f5db0689"}

experimental_model

Recombinant protein interaction and cluster-insertion analysis

exposure

NFU1-ISCA1 donor complex

limitations

Loading the radical-SAM site is distinct from recycling the auxiliary sulfur-donor site.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human proteins

plain_language

Protein-to-protein recognition helps deliver the cluster to the correct destination.

primary_references

[ala-p35343688] Protein-Interaction Affinity Gradient Drives [4Fe-4S] Cluster Insertion in Human Lipoyl Synthase. (2022). https://pubmed.ncbi.nlm.nih.gov/35343688/ DOI: 10.1021/jacs.1c13626

tissue_or_cell_type

LIAS radical-SAM site

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 377–388

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant protein interaction and cluster-insertion analysis · source_derived_draft · unverified_draft

### ala-nfu1-affinity-gradient The NFU1 C-domain guides cluster transfer along increasing interaction affinity from ISCA1 toward LIAS. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Protein-to-protein recognition helps deliver the cluster to the correct destination. organism: Human proteins tissue_or_cell_type: LIAS radical-SAM site experimental_model: Recombinant protein interaction and cluster-insertion analysis limitations: Loading the radical-SAM site is distinct from recycling the auxiliary sulfur-donor site. exposure: NFU1-ISCA1 donor complex evidence_span: {"source_cache": "artifacts/ala-research/35343688.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "62b2b8ddcff12b7264515cd251238a0f0e4dbe086fa72830ebff6e88f5db0689", "start_char": 0, "end_char": 670, "text_sha256": "62b2b8ddcff12b7264515cd251238a0f0e4dbe086fa72830ebff6e88f5db0689"} [ala-p35343688] Protein-Interaction Affinity Gradient Drives [4Fe-4S] Cluster Insertion in Human Lipoyl Synthase. (2022). https://pubmed.ncbi.nlm.nih.gov/35343688/ DOI: 10.1021/jacs.1c13626

availability_state

machinery_impairment Imported condition classification; unverified.

cross_nutrient

Endogenous lipoate synthesis is a separate requirement of the thiamine-dependent PDH pathway.

evidence

[{"paper_key": "mayr-2011-lias", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}]

experimental_model

Patient biochemical analysis.

limitations

Single patient; no proof of thiamine-treatment failure mechanism.

nutrient

Thiamine (vitamin B1) · Thiamine (vitamin B1)

nutrient_topic

Thiamine research collection; topical membership is not evidence of a direct dietary effect. · Thiamine (vitamin B1)

organism

Homo sapiens

plain_language

A B1-dependent pathway can fail because its lipoyl machinery is defective. This case does not show that adding thiamine corrects the defect.

primary_references

[mayr-2011-lias] Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation (2011). https://pubmed.ncbi.nlm.nih.gov/22152680/ DOI: 10.1016/j.ajhg.2011.11.011

tissue_or_cell_type

Muscle and cultured fibroblasts

trigger_kind

machinery_impairment Imported condition classification; unverified.

Thiamine: mechanisms, deficiency and nutrient interactions (2026-09-17) · lines 759–771

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Patient biochemical analysis. · source_derived_draft · unverified_draft

### b1-lias-defect-reduces-pdh The LIAS Arg249His patient had depleted protein-bound lipoyl signal and reduced PDH activity/pyruvate oxidation in investigated muscle and fibroblast preparations. Condition category: machinery_impairment nutrient_topic: Thiamine research collection; topical membership is not evidence of a direct dietary effect. plain_language: A B1-dependent pathway can fail because its lipoyl machinery is defective. This case does not show that adding thiamine corrects the defect. organism: Homo sapiens tissue_or_cell_type: Muscle and cultured fibroblasts experimental_model: Patient biochemical analysis. limitations: Single patient; no proof of thiamine-treatment failure mechanism. evidence: [{"paper_key": "mayr-2011-lias", "source_bundle": "artifacts/thiamine_metabolism_sources.json", "passage_ids": ["abstract"], "locator": "Primary publication abstract", "preservation": "Exact text retained in the source bundle; full source document retained when openly retrievable."}] cross_nutrient: Endogenous lipoate synthesis is a separate requirement of the thiamine-dependent PDH pathway. nutrient: Thiamine (vitamin B1) [mayr-2011-lias] Lipoic acid synthetase deficiency causes neonatal-onset epilepsy, defective mitochondrial energy metabolism, and glycine elevation (2011). https://pubmed.ncbi.nlm.nih.gov/22152680/ DOI: 10.1016/j.ajhg.2011.11.011

evidence_span

{"source_cache": "artifacts/ala-research/36281303.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f", "start_char": 0, "end_char": 1732, "text_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f"}

experimental_model

Purified human LIAS turnover and cluster-transfer assays

exposure

LIAS with candidate iron-sulfur cluster donors

limitations

Cell-free transfer distinguishes direct donor activity from upstream functions in intact cells.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human recombinant proteins

plain_language

A protein can be essential in cells without stimulating this isolated transfer step.

primary_references

[ala-p36281303] In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1. (2022). https://pubmed.ncbi.nlm.nih.gov/36281303/ DOI: 10.1021/acsbiomedchemau.2c00020

tissue_or_cell_type

Mitochondrial lipoyl synthesis machinery

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 338–349

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human LIAS turnover and cluster-transfer assays · source_derived_draft · unverified_draft

### ala-bola3-direct-assay-null BOLA3 did not directly enhance Fe-S cluster transfer from NFU1 or GLRX5 to LIAS in the purified assay. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A protein can be essential in cells without stimulating this isolated transfer step. organism: Human recombinant proteins tissue_or_cell_type: Mitochondrial lipoyl synthesis machinery experimental_model: Purified human LIAS turnover and cluster-transfer assays limitations: Cell-free transfer distinguishes direct donor activity from upstream functions in intact cells. exposure: LIAS with candidate iron-sulfur cluster donors evidence_span: {"source_cache": "artifacts/ala-research/36281303.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f", "start_char": 0, "end_char": 1732, "text_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f"} [ala-p36281303] In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1. (2022). https://pubmed.ncbi.nlm.nih.gov/36281303/ DOI: 10.1021/acsbiomedchemau.2c00020

evidence_span

{"source_cache": "artifacts/ala-research/36281303.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f", "start_char": 0, "end_char": 1732, "text_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f"}

experimental_model

Purified human LIAS turnover and cluster-transfer assays

exposure

LIAS with candidate iron-sulfur cluster donors

limitations

Cell-free transfer distinguishes direct donor activity from upstream functions in intact cells.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human recombinant proteins

plain_language

SAM supplies radical chemistry here; this reaction is not methyl-group transfer.

primary_references

[ala-p36281303] In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1. (2022). https://pubmed.ncbi.nlm.nih.gov/36281303/ DOI: 10.1021/acsbiomedchemau.2c00020

tissue_or_cell_type

Mitochondrial lipoyl synthesis machinery

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 286–297

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human LIAS turnover and cluster-transfer assays · source_derived_draft · unverified_draft

### ala-lias-sam-radical LIAS cleaves SAM to generate a 5-deoxyadenosyl radical that initiates hydrogen abstraction from the octanoyl substrate. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: SAM supplies radical chemistry here; this reaction is not methyl-group transfer. organism: Human recombinant proteins tissue_or_cell_type: Mitochondrial lipoyl synthesis machinery experimental_model: Purified human LIAS turnover and cluster-transfer assays limitations: Cell-free transfer distinguishes direct donor activity from upstream functions in intact cells. exposure: LIAS with candidate iron-sulfur cluster donors evidence_span: {"source_cache": "artifacts/ala-research/36281303.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f", "start_char": 0, "end_char": 1732, "text_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f"} [ala-p36281303] In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1. (2022). https://pubmed.ncbi.nlm.nih.gov/36281303/ DOI: 10.1021/acsbiomedchemau.2c00020

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/ala-research/39547509.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c914532ce06cd71fa946c3aa27935a85d94827215c74ae076a0eebb80ebb45bd", "start_char": 0, "end_char": 1884, "text_sha256": "c914532ce06cd71fa946c3aa27935a85d94827215c74ae076a0eebb80ebb45bd"}

experimental_model

Engineered bacterial ligase in human knockout cells and a modeled patient allele

exposure

Mitochondrially targeted engineered LplA expression

limitations

Experimental genetic engineering, not ordinary supplementation and not a treated-patient efficacy trial.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human cells with bacterial enzyme engineering

plain_language

Adding a new enzyme created a route that free supplementation alone did not supply.

primary_references

[ala-p39547509] Engineered bacterial lipoate protein ligase A (lplA) restores lipoylation in cell models of lipoylation deficiency. (2024). https://pubmed.ncbi.nlm.nih.gov/39547509/ DOI: 10.1016/j.jbc.2024.107995

tissue_or_cell_type

Lipoylation-null cell models and K562 cells

trigger_kind

machinery_impairment Imported condition classification; unverified.

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 559–570

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Engineered bacterial ligase in human knockout cells and a modeled patient allele · source_derived_draft · unverified_draft

### ala-lpla-lipoylation-rescue Engineered LplA restored lipoylation in MECR-, BOLA3-, FDX1-, LIAS- and LIPT1-knockout cell models. Condition category: machinery_impairment nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Adding a new enzyme created a route that free supplementation alone did not supply. organism: Human cells with bacterial enzyme engineering tissue_or_cell_type: Lipoylation-null cell models and K562 cells experimental_model: Engineered bacterial ligase in human knockout cells and a modeled patient allele limitations: Experimental genetic engineering, not ordinary supplementation and not a treated-patient efficacy trial. exposure: Mitochondrially targeted engineered LplA expression evidence_span: {"source_cache": "artifacts/ala-research/39547509.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "c914532ce06cd71fa946c3aa27935a85d94827215c74ae076a0eebb80ebb45bd", "start_char": 0, "end_char": 1884, "text_sha256": "c914532ce06cd71fa946c3aa27935a85d94827215c74ae076a0eebb80ebb45bd"} [ala-p39547509] Engineered bacterial lipoate protein ligase A (lplA) restores lipoylation in cell models of lipoylation deficiency. (2024). https://pubmed.ncbi.nlm.nih.gov/39547509/ DOI: 10.1016/j.jbc.2024.107995

evidence_span

{"source_cache": "artifacts/ala-research/36281303.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f", "start_char": 0, "end_char": 1732, "text_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f"}

experimental_model

Purified human LIAS turnover and cluster-transfer assays

exposure

LIAS with candidate iron-sulfur cluster donors

limitations

Cell-free transfer distinguishes direct donor activity from upstream functions in intact cells.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human recombinant proteins

plain_language

NFU1 replenishes the sulfur-supplying cluster.

primary_references

[ala-p36281303] In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1. (2022). https://pubmed.ncbi.nlm.nih.gov/36281303/ DOI: 10.1021/acsbiomedchemau.2c00020

tissue_or_cell_type

Mitochondrial lipoyl synthesis machinery

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 325–336

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Purified human LIAS turnover and cluster-transfer assays · source_derived_draft · unverified_draft

### ala-nfu1-aux-repair NFU1 forms a tight complex with LIAS and efficiently restores its auxiliary cluster during turnover in vitro. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: NFU1 replenishes the sulfur-supplying cluster. organism: Human recombinant proteins tissue_or_cell_type: Mitochondrial lipoyl synthesis machinery experimental_model: Purified human LIAS turnover and cluster-transfer assays limitations: Cell-free transfer distinguishes direct donor activity from upstream functions in intact cells. exposure: LIAS with candidate iron-sulfur cluster donors evidence_span: {"source_cache": "artifacts/ala-research/36281303.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f", "start_char": 0, "end_char": 1732, "text_sha256": "29a716d2027786ee1eefa5380aca1ddc035ec330409162f3d4e61db20015780f"} [ala-p36281303] In Vitro Demonstration of Human Lipoyl Synthase Catalytic Activity in the Presence of NFU1. (2022). https://pubmed.ncbi.nlm.nih.gov/36281303/ DOI: 10.1021/acsbiomedchemau.2c00020

evidence_span

{"source_cache": "artifacts/ala-research/35343688.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "62b2b8ddcff12b7264515cd251238a0f0e4dbe086fa72830ebff6e88f5db0689", "start_char": 0, "end_char": 670, "text_sha256": "62b2b8ddcff12b7264515cd251238a0f0e4dbe086fa72830ebff6e88f5db0689"}

experimental_model

Recombinant protein interaction and cluster-insertion analysis

exposure

NFU1-ISCA1 donor complex

limitations

Loading the radical-SAM site is distinct from recycling the auxiliary sulfur-donor site.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human proteins

plain_language

A separate assembly route equips the radical-generating site.

primary_references

[ala-p35343688] Protein-Interaction Affinity Gradient Drives [4Fe-4S] Cluster Insertion in Human Lipoyl Synthase. (2022). https://pubmed.ncbi.nlm.nih.gov/35343688/ DOI: 10.1021/jacs.1c13626

tissue_or_cell_type

LIAS radical-SAM site

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 364–375

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Recombinant protein interaction and cluster-insertion analysis · source_derived_draft · unverified_draft

### ala-nfu1-isca1-radical-site An NFU1-ISCA1 heterodimer delivers a [4Fe-4S] cluster to the radical-SAM site of LIAS. Condition category: normal nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: A separate assembly route equips the radical-generating site. organism: Human proteins tissue_or_cell_type: LIAS radical-SAM site experimental_model: Recombinant protein interaction and cluster-insertion analysis limitations: Loading the radical-SAM site is distinct from recycling the auxiliary sulfur-donor site. exposure: NFU1-ISCA1 donor complex evidence_span: {"source_cache": "artifacts/ala-research/35343688.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "62b2b8ddcff12b7264515cd251238a0f0e4dbe086fa72830ebff6e88f5db0689", "start_char": 0, "end_char": 670, "text_sha256": "62b2b8ddcff12b7264515cd251238a0f0e4dbe086fa72830ebff6e88f5db0689"} [ala-p35343688] Protein-Interaction Affinity Gradient Drives [4Fe-4S] Cluster Insertion in Human Lipoyl Synthase. (2022). https://pubmed.ncbi.nlm.nih.gov/35343688/ DOI: 10.1021/jacs.1c13626

availability_state

machinery_impairment Imported condition classification; unverified.

evidence_span

{"source_cache": "artifacts/ala-research/24334290.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2d6f134f9da5ac532fac9c58757e80a0b51c9912f8ddbec39eb81d1e81ccbfb2", "start_char": 0, "end_char": 2342, "text_sha256": "2d6f134f9da5ac532fac9c58757e80a0b51c9912f8ddbec39eb81d1e81ccbfb2"}

experimental_model

Variant nonketotic hyperglycinemia cohort and cell complementation

exposure

LIAS, BOLA3 or GLRX5 variants; lipoate and mitochondrially targeted lipoate in cells

limitations

Phenotypes varied; respiratory-chain function was preserved in this series, unlike some other Fe-S disorders.

nutrient_topic

Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. · Lipoic acid

organism

Human

plain_language

Delivering the molecule nearer mitochondria was still insufficient in these models.

primary_references

[ala-p24334290] Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. (2014). https://pubmed.ncbi.nlm.nih.gov/24334290/ DOI: 10.1093/brain/awt328

tissue_or_cell_type

Eight genetically explained patients within an eleven-person group

trigger_kind

machinery_impairment Imported condition classification; unverified.

Alpha-lipoic acid: cofactor assembly, redox signaling and nutrient interactions (2026-09-17) · lines 546–557

AI-assisted literature curation; primary study URLs and scope retained in the document and extraction. Not publisher full text. · supports · Variant nonketotic hyperglycinemia cohort and cell complementation · source_derived_draft · unverified_draft

### ala-variant-lipoate-no-rescue Neither lipoate nor mitochondrially targeted lipoate corrected the studied cellular lipoylation deficiency. Condition category: machinery_impairment nutrient_topic: Alpha-lipoic acid research collection; topical membership is not evidence of a direct dietary effect. plain_language: Delivering the molecule nearer mitochondria was still insufficient in these models. organism: Human tissue_or_cell_type: Eight genetically explained patients within an eleven-person group experimental_model: Variant nonketotic hyperglycinemia cohort and cell complementation limitations: Phenotypes varied; respiratory-chain function was preserved in this series, unlike some other Fe-S disorders. exposure: LIAS, BOLA3 or GLRX5 variants; lipoate and mitochondrially targeted lipoate in cells evidence_span: {"source_cache": "artifacts/ala-research/24334290.abstract.txt", "locator": "Exact primary indexed abstract; zero-based, end-exclusive Unicode character offsets", "file_sha256": "2d6f134f9da5ac532fac9c58757e80a0b51c9912f8ddbec39eb81d1e81ccbfb2", "start_char": 0, "end_char": 2342, "text_sha256": "2d6f134f9da5ac532fac9c58757e80a0b51c9912f8ddbec39eb81d1e81ccbfb2"} [ala-p24334290] Variant non ketotic hyperglycinemia is caused by mutations in LIAS, BOLA3 and the novel gene GLRX5. (2014). https://pubmed.ncbi.nlm.nih.gov/24334290/ DOI: 10.1093/brain/awt328