Gangliosides Synthesis / Salvage / Degradation, Sphingolipid base, Disease cascade, Glycolipid metabolism, GBA chaperone

Gangliosides table (continuing from previous capture)

			↑ GM1 → ↓ PD, ↓ aggregation of a-syn to cytotoxic fibrills) GM2 GM3	GD1b(abundant) GD2 GD3	GT3	(abundant, is involved in LTP, synaptic plasticity, and cognitive function)
Function	essential for myelination, neuritogenesis, synaptogenesis and signalling of the neurotrophic factor GDNF [42-44].
pathology	A reduction in GM1a levels was described in SN and occipital cortex from PD patients (GBA loss시 ↓ Ceramide 니까 이것도 주나보다) (Gangliosidosis의 예) Tay-Sacks disease: a genetic defect which leads to no functional hexosaminidase A produced → GM2 to accumulate in lysosomes → ganglion cells in the nervous system swell enormously, disturbing the normal functions of neurons.[3]
Synthesis	De novo synthesis (적음?)
		Steps
		1	Ganglioside biosynthesis starts with the formation of ceramide (Figure 9) at the cytoplasmic leaflet of the ER membrane [124-126]. The first step, the condensation of L-serine and a coenzyme A-activated fatty acid is catalyzed by the pyridoxal phosphate-dependent serine palmitoyltransferase (SPT The next step in sphingolipid biosynthesis is the NADPH-dependent reduction of 3-ketosphinganine to sphinganine by 3-ketosphinganine reductase, followed by acylation of sphinganine to dihydroceramides of different chain lengths [131] During salvage, also other sphingoid bases are acylated by N-acyltransferases of the Lass family. Dihydroceramides are dehydrogenated to ceramide by the dihydroceramide desaturase des1 [134], or hydroxylated to phytoceramides by des2.
		2	stepwise transfer of nucleotide-activated monosaccharide units first on ceramide with growing glycan chains.
		3	stepwise transfer of nucleotide-activated monosaccharide units on GSLs with growing glycan chains.
	The B4GALNT1 gene encodes the enzyme, ((Huebecker et al. 2019, PMID 31703585) this encodes GM2 synthase) β-1,4-N-acetyl galactosaminyltransferase 1 (GalNac-T), which catalyzes the transfer of N-acetyl galactosamine onto GM3 and GD3 gangliosides → resulting in GM2 and GD2 → that then undergo further metabolism into GM1 and GD1 (Forsayeth and Hadaczek 2018, PMID 29459819)

Salvage pathway / Degradation

	[salvage pathway (from recycling): this can be predominant undifferentiated cells (?)]
	Steps
	1	GlcCer 생성 (원래 알고 있는 pathway) on the cytoplasmic face of Golgi (membrane) (by Transfer of a glucose residue from UDP glucose to ceramide)
	2	GlcCer is translocated to the luminal site of the Golgi membrane
	3	LacCer is formed from GlcCer (by galactosyltransferase I) LacCer and its sialylated derivatives, the hematosides GM3, GD3, and GT3 (Figure 11) serve as precursors for complex gangliosides of the O-, a-, b-, and c-series. part of the GlcCer pool can reach the cytosolic leaflet of the plasma membrane where it can be degraded by the β-glucosidase Gba2 [185
Degradation	degraded to ceramides by sequential removal of sugar units in the oligosaccharide group, catalyzed by a set of highly specific lysosomal enzymes.

Sphingolipid base structure

Sphingolipid figure labels: Sphingosine (C18), fatty acid, head group, Sphingolipid.

Name	X=
Ceramide	H
Sphingomyelin	~P~Choline ~P~Ethanolamine
Glucosylcerebroside	—Glc (in non-neural tissue)
Galactocerebroside	—Gal (in neural tissue)
Globosides	several neutral sugars (Glc, Gal, GalNAc)
Gangliosides	complex carbohydrates: GM: single NANA GD: two NANA GT: three NANA GQ: four NANA

N-acetylneuraminic acid (NANA) figure label: N-acetylneuraminic acid (NANA).

Ganglioside / sphingolipid degradation cascade (figure labels)

• GM1: Ceramide–Glc–Gal–GalNAc–Gal, side branch NANA; arrow with enzyme β-galactosidase, disease GM1 gangliosidosis, releasing Gal → Ceramide–Glc–Gal–GalNAc.
• GM2: Ceramide–Glc–Gal–GalNAc, side branch NANA; arrow with enzyme hexosaminidase A, disease Tay-Sachs disease, releasing GalNAc → Ceramide–Glc–Gal.
• GM3: Ceramide–Glc–Gal, side branch NANA; arrow with enzyme ganglioside neuraminidase, releasing NANA → Ceramide–Glc–Gal.
• Globoside: GalNAc–Gal–Gal–Glc–Ceramide; arrow with enzyme hexosaminidase A + B, disease Sandhoff-Jatzkewitz's disease, releasing GalNAc → Gal–Gal–Glc–Ceramide.
• Gal–Gal–Glc–Ceramide → Ceramide–Glc–Gal; arrow with enzyme alpha-galactosidase A, disease Fabry's disease, releasing Gal.
• Ceramide–Glc–Gal → Ceramide–Glc; arrow with enzyme β-galactosidase, releasing Gal.
• Ceramide–Glc → Ceramide; arrow with enzyme glucocerebrosidase, disease Gaucher's disease, releasing Glc.
• Ceramide ← ceraminidase Farber's disease ← (Ceramide arm at right) ; outgoing Sphingosine + fatty acid.
• CholinePCeramide ↔ Ceramide via sphingomyelinase, disease Niemann-Pick disease; co-product Phosphocholine. (Sphingomyelin label visible at the right edge.)
• Cerebroside arm: Ceramide–Gal → Ceramide; arrow with enzyme Gal-cerebroside-β-galactosidase, disease Krabbe's disease, releasing Gal.
• Ceramide–Gal → Ceramide–Gal~S (Sulphatide); arrow with enzyme cerebroside sulphatase, disease metachromatic leucodystrophy, side group SO₄²⁻.

Glycolipid metabolism schematic

위 그림에서 cerebroside 는 = GlcCer, GalCer

Glycolipid metabolism figure labels and arrows:

• Glucosylceramide ↔ Ceramide via GluCer synthase (forward) / GCase (reverse)
• Galactosylceramide ↔ Ceramide via GalCer synthase (forward) / GalCeramidase (reverse)
• Glucosylceramide → Lactosylceramide via LacCer synthase
• Lactosylceramide → Gangliosides via Sialyl Transferase
• Ceramide ↔ Sphingomyelin via SMase (Sphingomyelin → Ceramide) / SMS (Ceramide → Sphingomyelin)

Caption (under the figure):

…de and glycolipid metabolism. Products are indicated in bold and italics. Abbreviations for enzymes are as follows: GCase: ; GalCer synthase: galactosylceramide synthase; GluCer synthase: glucosylceramide synthase; GalCeramidase: galactosyl synthase: Lactosylceramide synthase; SMase: Sphingomyelinase; SMS: Sphingomyelin synthase. pone.0073094.g001

GlcSph inset (GBA1 cycle)

GlcSph inset figure labels:

• GlcCer ↔ GlcSph (annotated (C 18:0)) ↔ GlcCho
• GalSph ↔ GalCer (annotated (C 24:1)) ↔ Cer ↔ Sph
• GBA1, EC 3.2.1.45 shown as a wide rectangle gating the GlcSph → GlcCho and Cer → Sph reactions
• Filled red ↑ and hollow ↑ arrows annotate disease-level direction beside GlcSph, GalCer, GlcCer, Cer, and Sph

GBA chaperone to increase GBA functions

Chaperone box figure labels and structures:

• Isofagomine (GD, failed in Ph-2) — chemical structure with HO, NH, OH groups on a ring.
• Ambroxol (GD/PD, Ph-2) — chemical structure with Br substituents on an aromatic ring, plus an NH₂ amine and HO-N alkyl tail.

Reaction cartoon below the chaperones:

• GluCer (skeletal structure with Sphingosine + fatty acid + Glu sugar) + GBA → Glucose + Ceramide
• Reverse arrow labelled GlcCer synthase (GCS)

Uncertain Spans

location	transcription	uncertainty
Gangliosides table top continuation	column-header alignment for the right-most columns (GD1b(abundant) / GD2 / GD3, GT3, (abundant, is involved in LTP...))	the table header row is clipped at the top of this capture; the column count is taken from the matching table in 20240722_182207 (One/Two/Three/Four NANAs).
Synthesis step 1	pyridoxal phosphate-dependent serine palmitoyltransferase (SPT	the closing ) after SPT is missing in the source.
salvage step 3	complex gangliosides of the O-, a-, b-, and c-series.	the leading character reads as alphabetic O; PaddleOCR alternates with the digit 0.
GlcSph inset	(C 18:0) and (C 24:1)	small annotations next to GlcCer and GalCer in the inset; preserved as visible.
GBA chaperone reaction	GluCer + GBA → Glucose + Ceramide; reverse GlcCer synthase (GCS)	the forward and reverse arrows partly overlap the structural drawings; the forward direction reads GluCer → Glucose + Ceramide via GBA.